European Projects
Development of less toxic and more effective biopesticides for the treatment of crops and harvests that allow the development of sustainable agriculture (MACBIOPEST).
Reference: MAC2/1.1a/289
Period: 10/01/2019 to 09/31/2022
Financing granted: €869,150
IP: Isabel López Bazzocchi
SUMMARY: This project unites the cultural, natural, and scientific-technical heritage of the Macaronesian region to address one of our society's most pressing problems: obtaining more effective and safer plant protection agents, from both a health and ecological perspective, that contribute to sustainable growth. On the one hand, the consolidation of the Knowledge Bank, which will be expanded with information from the other archipelagos of the Macaronesian region, will allow for the safeguarding of cultural heritage. On the other hand, this information will constitute an unparalleled starting point for the selection of the plants and microalgae under study, using environmentally friendly techniques. Improving the activity, specificity, and bioavailability of the extracts for the treatment of the main pests affecting crops will be a priority objective for their application and subsequent commercialization.
National Plan Projects
Sustainable chemistry: from small molecules to complex functional systems
Subproject 1
Reference: PGC2018-094503-B-C21
Period: 01/01/2019 to 12/31/2021
Financing granted: €119,790
IP: Tomás Martín Ruiz and Romen Carrillo Fumero
Subproject 2
Reference: PGC2018-094503-B-C22
Period: 01/01/2019 to 12/31/2021
Financing granted: €119,790
IP: Juan Ignacio Padrón Peña and Víctor Sotero Martín García
SUMMARY: Sustainability is a multifaceted and cross-cutting concept that has become increasingly essential over time. Sustainable chemistry requires new approaches to organic synthesis to access novel molecular architectures with well-designed functional properties. Consequently, the challenges of organic chemistry have adapted to the changing times, shifting from simply constructing any imaginable molecular architecture to designing new chemical processes that, in addition to being efficient and selective, must be environmentally friendly, scalable and cost-effective, instrumentally simple, and amenable to implementation in practical total synthesis programs. At the same time, modern organic chemistry demands increasingly complex systems for increasingly sophisticated tasks and functions. Therefore, this coordinated project aims to address a considerable range of these challenges through three fundamental axes: catalysis, molecular construction of small molecules, and synthesis and applications of functional systems. Within this coordinated effort, we will focus, first and foremost, on various facets of catalysis, from organocatalysis to sustainable metal catalysis (salt and iron metal complexes) along with domino processes, in order to explore and optimize certain methodologies and apply them to construct molecular libraries. Particular emphasis will be placed on diversified total synthesis and diversity-oriented synthesis programs, as well as on sustainability throughout the project. These libraries, together with rational molecular modifications, will help us discover and enhance biological activities, particularly with regard to cancer and Alzheimer's disease. Furthermore, complex functional architectures will be designed and synthesized with the aim of intelligently controlling these chemical systems, for better interaction with biological environments or to improve physicochemical properties. In this respect, novel hybrid haptens, self-immolating prodrugs, and stimulus-responsive superstructures will be studied, and their effects on biological systems will be explored. Consequently, this proposal will almost certainly provide significant advances, given its global vision and the multiple approaches adopted to address the challenges facing organic chemistry today.
Search and identification of new small-molecule modulators of therapeutic targets in cancer
Reference: RTI2018-094356-B-C21
Period: 01/01/2019 to 12/31/2022
Financing granted: €181,500
IP: Ana Estévez-Braun
SUMMARY: The main objectives of this project include the identification and preclinical pharmacological evaluation of original bioinspired products that could be effective in the treatment of diseases related to the proteins STAT3/5, YAP1 or ER. Under physiological conditions, these proteins control cell growth, survival, differentiation, metabolism or inflammatory/immunomodulatory cell response. In contrast, aberrant activation of these proteins is associated with the development of leukemias, chronic myeloproliferative syndromes, breast and prostate cancers, pathological immune responses together with resistance mechanisms to current treatments. The absence of treatments with an acceptable therapeutic window and the appearance of resistance to treatment, have awakened a high demand for finding new compounds capable of inhibiting/modulating the activities of STAT3/5, YAP1 or ER, in the context of the aforementioned diseases. Thus, we will use structural motifs present in natural bioactive products and their analogues through the use of effective strategies These strategies include domino and/or multicomponent reactions and the diversity-oriented synthesis based on privileged structures (p-DOS). Products obtained from natural sources will also be tested, since Nature can provide variants of structures to which our inspiration when carrying out chemical modifications is not able to reach.
These strategies will be combined with in silico modeling studies. Specifically, molecules derived from heterocyclic naphthoquinones, will be evaluated as inhibitors of STAT3/5; N-substituted-3,5-diarylpyrazoles, as SERM-type molecules; flufenamic acid derivatives as YAP1 inhibitors. Metallic complexes of bioactive bidentate ligands will also be examined. To effectively identify chemical modulators that act at any level of the proteins STAT3/5-, YAP1- or ER-dependent signaling cascade, or molecules with anti-inflammatory or immunomodulatory activities, we firstly will use screening systems based on reporter genes. Secondly, we will evaluate cytotoxic/antiproliferative activities of the selected molecules with real-time-based analysis systems in cell models dependent on aberrant activity of STAT3/5 (K562, TNBC), YAP1 (LNCap, TNBC) or RE (MCF7-BUS), as well as in primary non-tumor cells. The screening of anti-inflammatory capacity of chemical libraries will be real-time performed by using reporter macrophages. The E-Screen assay will provide the selected SERM-like products. Third, we will gather the most potent and least toxic products evaluated in vitro, to carry out more detailed mechanistic studies. These studies will report any relevant biological phenomena related to antitumor, anti-inflammatory, immunomodulatory, and SERM-type effects of the selected molecules: cell cycle, apoptosis, migration, 3D cell culture (spheroids), colony growth, macrophage functionality (in bone marrow derived- and tumor associated macrophages) or bone calcification. Finally, predictive pharmacogenomic studies on representative disease cellular models will lead to select optimal molecule(s) to evaluate in vivo (bioavailability, efficacy, acute toxicity). The most active molecules will be optimized in silico, which facilitate the rational design of new entities.
Preparation of the MSC-ITN action “Multitargeted therapies against pancreatic ductal adenocarcinoma (PANCNET)”
Reference: EIN2019-102928
Period: 06/01/2019 to 05/31/2022
Financing granted: €16,200
IP: José M. Padrón
SUMMARY: The specific objective of this action is to prepare a proposal for a Marie Skłodowska-Curie ITN Action in transnational collaboration, coordinated by the University of La Laguna. The action, known by the acronym PANCNET, will be submitted in the next call for proposals for the program (H2020-MSCA-ITN-2020), which is expected to take place in the last quarter of 2019. The goal of PANCNET is to train ten researchers in multi-target therapies for pancreatic ductal adenocarcinoma (PDAC) through a multidisciplinary and international network of public and private centers. The knowledge generated will be transformed into products and services for the economic and social benefit of the European Union.
The strategic aim of this proposal is to gain access to the coordination and leadership of major international projects. The consortium comprises nine academic partners (universities and research institutes) and four companies. The academic participants in this consortium come from four EU member states (Spain, Portugal, Italy, and Malta) and three associated states (Norway, Israel, and Serbia). The companies participating in the consortium are spinoffs from universities in Spain, Italy, and Austria. The academic partners will be responsible for recruiting researchers (and will receive EU funding), while the companies will host doctoral students for their off-campus training. The consortium was established based on the relationships forged by the participating Spanish groups. These contacts were obtained through participation in various European networks known as COST Actions. With the exception of the Israeli group and Orfan Biotech, the other consortium participants are currently involved or have previously collaborated with the principal investigator on various COST Actions. The contact with the Israeli group predates this collaboration and stems from Professor Yehuda Assaraf and the Principal Investigator's membership in the Pharmacology and Molecular Mechanisms (PAMM) group at the EORTC. Orfan Biotech is a spin-off company founded by Dr. Miguel X. Fernandes, one of the researchers in the applicant ULL group. All participating partners have a proven track record in the PANCNET thematic areas and their institutions possess the necessary resources to carry out the project.
Climate-human interactions in central Mediterranean Iberia during MIS 4 (IBEMIS4)
Reference: PID2019-107113RB-I00
Period: 07/01/2020 to 12/31/2024
Financing granted: €84,700
IP: Carolina Mallol
SUMMARY: Gaining detailed knowledge about regional variation in the extent and effects of past global climate warming/cooling periods on humans is important to broaden our perspective on the impact of climate change today. The Iberian Peninsula is located at the climatically mild, southernmost latitudes of Europe and represents a cul-de-sac for population dynamics prior to navigation technology. For these reasons, it has been central to paleoclimate and human evolution research. Specifically, debates on Neanderthal population dynamics and disappearance have focused on archaeological and paleontological evidence from Spain and Portugal and there are several interpretations of Neanderthal disappearance based on the Iberian Peninsula as a climatic refuge, particularly in the south. Recent site-specific paleoenvironmental investigations including our own, corroborate the distinct character of the Mediterranean rim of Iberia as a glacial refugium during cold periods. These studies show that the climatic context of this region did not change significantly during cold periods and possibly, the Neanderthal population was more stable there than in more northern latitudes where climate change had more drastic effects. However, this hypothesis remains untested because most of the research on Iberian Neanderthals has focused on Neanderthal disappearance and thus, has been carried out in more recent sites (MIS 3). Studies at high temporal resolution (less than five thousand years) on earlier Neanderthal sites, particularly those covering transitions between different climate stages (eg, MIS 6 – MIS 5, MIS 5- MIS 4, MIS 4 – MIS 3) are to build a robust dataset on past climate change and its effects on human populations. This project has a focus on climate-human interactions in the Iberian Mediterranean rim during MIS 4. The project aims to implement a hindcast approach to better understand periods of global climate change and gain insight into human nature by turning to an example from the Palaeolithic. We will apply a multidisciplinary, high-temporal resolution strategy to the study of the MIS 4 period in two Neanderthal contexts within the central Iberian Mediterranean rim.
Bioactive molecules from marine microalgae
Reference: PID2019-109476RB-C21
Period: 06/01/2020 to 12/31/2022
Financing granted: €133,100
IP: José J. Fernández and Antonio Hernández Daranas
SUMMARY: Marine microalgae are a source of a wide variety of compounds of commercial interest. In particular, some species belonging to the Haptophyta and Dinoflagellata groups have demonstrated the ability to generate natural compounds with extremely complex structures and potent biological activities, making them very useful tools for analyzing cellular processes and with potential applications in the agri-food sector. However, most of these molecules have not progressed beyond discovery due to their low availability in the natural environment, the serious difficulties encountered in their large-scale and intensive cultivation, and the impossibility of their chemical synthesis given their high structural complexity. In this context, the coordinated BIOALGRI project combines the necessary synergies and experience of the ULL-IPNA and UAL groups to advance the industrial development and utilization of bioactive molecules produced by marine microalgae for agri-food applications, using photobioreactors and continuous cultures at medium and large scales. A thorough screening will be conducted to identify new, productive strains, focusing on those that are easier to cultivate and capable of producing bioactive substances of interest. Through the development of advanced cultivation protocols, including variations in stress conditions and the use of elicitors (OSMAC) at pilot scale, the aim is to establish optimal conditions for continuous and highly productive biomass cultivation within a biorefinery framework using biocompatible solvents. Extraction and isolation processes for the substances of interest will also be developed, as well as the utilization of cellular waste, contributing to the overall valorization of the bioprocess within a circular economy framework.
All phases are designed in a bioguided manner, supported by an extensive battery of in vitro and in vivo biological assays to assess their phytosanitary action in products easily transferable to industry. This work includes the structural elucidation and determination of the configuration of these highly complex molecules, primarily using NMR and the design of new structural resolution methodologies. In this project, we also propose the optimization of Gambierdiscus cultures, which produce neurotoxins related to ciguatera, an emerging contaminant in tropical and subtropical fish affecting the Canary Islands. The aim is to identify new toxins and develop reference standards that are in high demand in the EU and currently unavailable. The project also includes the generation of antibodies to help develop a rapid diagnostic kit for contaminated fish. The study of the modes of action of the isolated molecules will be carried out using artificial membranes and/or biological models with atomic force microscopy techniques.
BIOALGRI aims to contribute and provide knowledge to achieve the objectives defined for the societal challenges "Food quality and safety, productive and sustainable agricultural activity, sustainability of natural resources, marine and maritime research" and "Climate change and efficiency of resources and raw materials" established by Horizon 2020 and the Framework Programme for Research and Innovation 2014-2020.
Development of gel-based formulations for redox catalysis based on triplet-triplet annihilation using visible light
Reference: PID2019-105391GB-C21
Period: 06/01/2020 to 05/31/2023
Financing granted: €133,100
IP: David Díaz Díaz
SUMMARY: The main objective of subproject 1 is the development of stable gel formulations for use as reaction media for two-photon photo-redox catalysis in the absence of metals and using visible light under aerobic conditions. The complexity and main challenges associated with this project lie in the multivariable study that must be carried out to implement the proposed methodology as generally as possible in the field of photo-redox catalysis. In general, nanostructured viscoelastic gels have high potential to mimic the compartmentalization found in complex natural systems in order to carry out photochemical reactions that would otherwise be more difficult to perform. Furthermore, their high surface areas, remarkable diffusion properties, gel-sol reversibility, structural and functional tuning capabilities, and responsiveness to multiple stimuli are some of the essential characteristics of many of these fascinating materials. Such properties offer a versatile platform for overcoming some significant disadvantages of other confined media. In this context, and in comparison with other photocatalytic protocols, the use of gels as reaction media has great potential to facilitate the activation of some bonds with certain advantages such as the possibility of carrying out the reactions under very mild conditions (visible light, room temperature, atmospheric pressure and aerobic conditions), use of metal-free photocatalysts and the absence of additives (sacrificial donors/acceptors) in the gel medium.
This subproject is based on a multidisciplinary approach that requires considerable knowledge and experience in organic chemistry, soft materials, colloidal chemistry, and photocatalysis. To achieve the main objective of this subproject, the following specific objectives will be pursued:
1) Development of hybrid gels for the accumulation of light energy, which involves the manufacture and characterization of stable formulations containing specific donor/acceptor pairs.
2) Validation of biphotonic conversion to higher frequency (vis-to-UV) coupled to an electron transfer to achieve different synthetic objectives within the gels mentioned above and which have been prepared in the presence of appropriate substrates.
3) Development and validation of stable hydrogels for biphotonic redox catalysis in water.
4) To understand through a multivariable study the role of the gel matrix with regard to its effect on reaction performance, kinetics and selectivity.
5) Demonstration of the scalability of the process under continuous flow conditions using a biohydrogel containing specific donor/acceptor pairs as a nanoreactor.
Regional Projects
New therapeutic strategies for the treatment of pancreatic cancer (TheraPanc)
Reference: ProID2020010101
Period: 01/01/2020 to 09/30/2022
Financing granted: €70,000
IP: José M. Padrón
SUMMARYPancreatic ductal adenocarcinoma (PDAC) is a relatively rare tumor (21% of all cancer cases), but it is the fifth leading cause of cancer death worldwide. The median survival time after a PDAC diagnosis is less than one year, and the average lifetime risk of developing PDAC is 1 in 78. Some of the factors that make PDAC such an aggressive cancer include: late diagnosis (due to the absence of symptoms and 24 biomarkers for early detection), the pancreas's difficult anatomical location, metastatic spread when the primary tumor is too small to be detected, the dynamic interaction of the tumor with stromal cells (which create a dense fibrous cap around the tumor), and the limited effectiveness of existing therapies. The overall goal of the TheraPanc project is to demonstrate, in a preclinical setting, that inhibiting glutamine metabolism with small molecules blocks PDAC growth. At TheraPanc, we will focus on proposing predictive biomarkers and developing a new therapy to treat PDAC that targets how PDAC cells obtain the energy they need to proliferate. The TheraPanc project is developing a new, more effective, and better-tolerated therapy for pancreatic cancer, with the ultimate goal of improving survival and quality of life for patients with this malignancy.
Blue biotechnology: bioprospecting and development of the biomedical potential of microalgae from the Canary Islands of the genus Amphidinium
Reference: ProID2020010123
Period: 01/01/2020 to 09/30/2022
Financing granted: €68,500
IP: María Luisa Souto Suárez
SUMMARYThe oceans harbor a vast array of organisms, offering a biological and chemical diversity that makes them an attractive resource for biotechnological applications. This biodiversity has endowed marine organisms with unique characteristics that allow them to synthesize bioactive compounds of great interest. The European Union, within its Horizon 2020 Research and Innovation program, has established the so-called "Blue Bioeconomy" or "Blue Growth" as one of its strategic priorities, stating that the sustainable and competitive exploitation of seas and oceans should influence Europe's economic recovery and contribute to human well-being and health. The knowledge generated through marine biodiversity research should benefit areas such as sustainable fishing, aquaculture, and marine biotechnology, not to mention the applications that can arise from the isolation of the natural products they produce in biomedicine, human health, industrial processes, and clean energy.
In this context, the Canary Archipelago and its marine resources can undoubtedly play a key role, as is clearly reflected in the aspects of interest of this call, by being able to prioritize among its lines of research projects that explore the innovative, sustainable and respectful use of marine biomass from primary production to processing and generation of value-added products within the marine bioeconomy.
Marine microalgae from the dinoflagellate group are a largely untapped source of biotechnological applications. This is because, for decades, they have presented serious difficulties for large-scale and intensive cultivation, resulting in low yields of biomass and bioproducts.
Dinoflagellates produce a wide variety of substances with extremely complex structures and potent pharmacological activities, making them enormously useful tools for studying cellular processes. Despite the interest in these substances, very few are commercially available, and those that are are always obtained from specialized laboratories and at very high prices.
Building on our previous work, this project aims to bioprospect for dinoflagellate strains of the genus Amphidinium in Canary Island waters for their biotechnological application in the industrial-scale production of high-value-added substances. We are particularly focused on the production of amphidinol-type secondary metabolites for their potential therapeutic applications, including the treatment of tropical diseases, through close collaboration with groups at the Institute of Tropical Diseases-ULL.
The objectives include selecting strains that are super-producers of amphidinols, developing protocols and methodologies to provide sufficient quantities of amphidinols for structural elucidation, for their application as analytical standards, for conducting mode-of-action studies, and for laying the groundwork for the application of their bioactive potential. Furthermore, the project envisions developing treatments that allow for the comprehensive utilization of the biomass and culture medium after the extraction of the metabolites of interest, in order to achieve maximum added value.
This project will contribute to developing the potential of the marine resources of the Canary Islands in a sustainable and respectful manner and to boosting the commercial exploitation of dinoflagellates and their derived bioproducts as part of the bioeconomy based on Blue Biotechnology.
Asymmetric organocatalysis. Towards a more sustainable chemistry (ORCHISES)
Reference: ProID2020010004
Period: 01/01/2020 to 09/30/2022
Financing granted: €70,000
IP: Tomás Martín Ruiz
SUMMARYThe project focuses on developing highly sustainable chemical processes using an approach based on asymmetric organocatalysis. This discipline aligns with many of the fundamental principles of green chemistry and relies on developing simple molecular systems that mimic the chemistry of enzymes. Enzymes are the catalysts for chemical processes in living organisms. They operate with very low catalytic charges, are extremely selective, and function under environmentally friendly reaction conditions. However, enzymes are scarce, difficult to purify, and structurally complex, making them less suitable for synthesizing high-demand chemicals. In contrast, organocatalysts act as isolated active sites of enzymes, reducing their specificity and thus making them more attractive to industry. In our research group, we have developed two complementary bifunctional organocatalysts that enable reactions with low catalytic loading (< 1 mol⁻¹TP⁻³T), generating products with high yields (> 911TP⁻³T) and excellent enantiomeric excesses (> 971TP⁻³T). Our objective is to anchor these catalysts to a solid support, allowing us to perform the reactions in a heterogeneous phase and thus recover and reuse the organocatalysts supported on the solid phase through simple filtration. This will also facilitate the isolation of the final product. These supported catalysts will also allow us to perform the chemical reactions continuously (flow chemistry). Furthermore, we aim to extend the use of these catalysts, both in solution and in a heterogeneous phase, to other types of asymmetric reactions, enabling us to obtain high-value-added products in a few reaction steps and with high enantiomeric purity.
Search for new inhibitors of antitumor targets from biodiversity-based chem libraries
Reference: ProID2017010071
Period: 09/01/2017 to 04/30/2021
Financing granted: €69,999
IP: Ana Estévez-Braun
SUMMARYThe objective of this project is the search for and identification of novel inhibitors of antitumor targets from Biodiverse Chemolibraries. These chemolibraries will be prepared using different types of natural products as a starting point, following various effective strategies for analog preparation, such as domino and/or multicomponent reactions, or the complexity-to-diversity (CtD) approach, among others. The different series will be evaluated against the cancer targets of interest that are the subject of this project (estrogen receptors, the JAK-STAT signaling pathway, and bromodomains) after a preliminary review of the literature and docking modeling studies of the target structures available in the Protein Data Bank (PDB). Based on the results obtained after the biological evaluation, new analogs will be designed using in silico studies to identify compounds with improved activity, selectivity, and ADME/TOX properties.
Evaluation of Canary Island endemic species as a source of biomolecules of interest (EVECAN)
Underwater mapping studies for bioprospecting in search of products and species with pharmacological potential and climate change experiments
Reference: EATIC2020010054
Period: 01/01/2020 to 07/15/2021
Financing granted: €66,443.38
IP: CIMA SL
Participating IUBO researchers: José J. Fernández, María L. Souto, Ana R. Díaz-Marrero, Nathália P. Nocchi
SUMMARYIn recent decades, the number of studies on deep-sea Atlantic coral communities has increased due to technological advancements. However, there is still a need to expand our knowledge of these communities, as reflected in the European Union's Horizon 2020 program, which highlights the role of deep-sea coral communities as bioconstructors and biodiversity hotspots, as well as refuge and nursery grounds for diverse species. Many marine microorganisms are used in the development of new drugs, serving as target organisms for obtaining substances of pharmacological or industrial interest. In the Canary Islands, one of the key species in deep-sea coral ecosystems is the species Dendrophyllia ramea, This species, which can be found at depths of 60 meters or more, appears to possess all the characteristics (wide distribution, capacity as a "bio-constructor" for the formation of large, complex forests) necessary for conducting experimental studies on the ecophysiological responses of this deep-sea coral species to different environmental conditions predicted in future climate change scenarios, such as ocean warming and acidification. These experiments will allow us to determine the species' recovery time and resilience to climate change conditions, enabling us to predict the potential effects of climate change on D. ramea populations under the scenarios projected by the Intergovernmental Panel on Climate Change (IPCC).
Search, synthesis and preclinical evaluation of new molecules that modulate the JAK-STAT pathway as antitumor and/or anti-inflammatory agents.
Reference: ProID2021010037
Period: 05/01/2021 to 04/30/2023
Financing granted: €70,000
IP: Ana Estévez Braun
SUMMARYThe objective of this project is the search, identification, and preclinical evaluation of new antitumor and/or anti-inflammatory agents. We intend to identify new chemical entities that inhibit/modulate the pro-tumor and/or pro-inflammatory activities of the JAK2, STAT3, and STAT5 proteins, which are of interest in the treatment of different types of cancer, both hematological and non-hematological, in the regulation of macrophage phenotypes (pro-inflammatory, pro-tumor), and the aberrant pro-inflammatory response (cytokine storm), or pathologies resistant to primary drug therapy. For this purpose, chemical libraries obtained from efficient synthetic strategies and designed based on previous research and molecular modeling studies on targets involved in the JAK/STAT pathway will be used. Medium- to high-throughput methods will be employed to screen the chemical libraries, allowing for automated and simultaneous analysis in a single real-time assay. These automated screening procedures will implement the evaluation and quantification of phenotypic changes in 2D and 3D cell models (spheroids) representative of myeloid leukemias and triple-negative breast cancer, as well as immortalized macrophages. To identify potential inhibitors or modulators of transcriptional activities dependent on the STAT3, STAT5, or NF-κB proteins, cell line systems stably transfected with reporter genes activated by these transcription factors will be used. These studies will allow the selection of lead molecules based on their antitumor and/or anti-inflammatory-immunomodulatory efficacy, and their best ADMET profiles, to carry out more detailed mechanistic studies that will help establish their efficacy and toxicity. in vivo.
Projects co-financed by the Tenerife Island Council
Aboriginal paleoenvironmental contexts and their management. Some island examples (PALEOCAN)
Reference: 2018PATRI19
Period: 03/01/2019 to 03/01/2021
Funding received: €54,000
IP: Carolina Mallol Duque
SUMMARYThe aboriginal settlement of the Canary Islands has been the subject of extensive research by our team for several decades. As a result, some of the sites we have worked on have provided a significant portion of the documented human record for the pre-European period of the islands of Tenerife, La Palma, and La Gomera.
Since these excavations ceased, and especially in recent years, archaeology as a scientific discipline has undergone an extraordinary methodological revolution with the development of high-resolution analytical techniques aimed at exploiting the archaeological record at the microscopic and molecular scale. This has yielded invaluable information about the processes of site formation, paleoenvironmental conditions, taphonomic issues, and anthropogenic dynamics.
Despite its enormous potential, archaeology in the Canary Islands has not yet fully integrated and consolidated such intervention protocols. Therefore, in recent years we have undertaken a series of joint projects whose main objective is to implement high-resolution geoarchaeological techniques at various sites on different islands. The studies are still underway, and although the sampling and sample processing phase has been successfully completed, the results, still preliminary, have not yet been published. The analyses are being carried out at the Micromorphology and Archaeological Biomarkers Laboratory (AMBI Lab) of the University of La Laguna, located at the Antonio González University Institute of Bio-organic Chemistry (IUBO).
The purpose of this project is to complement existing research through: 1) a sclerochronological study at the Las Estacas site (Buenavista del Norte, Tenerife) and 2) lipid biomarker analysis at the Roques de García Volcanic Tube (Cañadas del Teide, Tenerife), Belmaco (Villa de Mazo, La Palma), and Buracas (Garafía, La Palma). The data obtained through this project and the resulting information will lead to high-impact scientific publications, with corresponding dissemination at local and international conferences, thereby promoting the pre-Columbian heritage of the Canary Islands and the current archaeological work being carried out to understand, disseminate, and protect it. The definitive incorporation of a series of fundamental analytical techniques into archaeological practice in the Canary Islands, aimed at optimizing the scientific and heritage exploitation of the island sites, will in turn result in an intervention model that can be applied to any site in the islands.
Search, design and synthesis of new antitumor agents that inhibit bromodomains and the JAK-STAT oncogenic pathway
Reference: Agustín de Betancourt Project
Period: 01/01/2019 to 12/31/2022
IP: Ángel Amesty Arrieta
IP-ULL: Ana Estévez Braun
SUMMARYCancer is a very common disease today and, according to the World Health Organization (WHO), is one of the leading causes of death worldwide. Around 14.1 million people were diagnosed with cancer in 2015. A bromodomain (BRD) is a structural module composed of approximately 110 amino acids found in various proteins involved in transcriptional activation. It is a specific protein-protein interaction domain. Members of this family include BRD2, BRD3, BRD4, and BDRT, which perform diverse functions in the regulation of transcription by RNA polymerase II. The importance of designing and searching for new molecular entities that inhibit bromodomains is correlated with the role these targets play in cell cycle control, as they are critical in affecting cellular processes such as cell proliferation, apoptosis, and transcription. The STAT protein family, especially STAT1, STAT3, and STAT5, is involved in regulating cell growth, differentiation, immune response, and survival. In recent years, they have also been shown to be key in the pathogenesis of various diseases, such as cancer. Under physiological conditions, the upregulation (activation) of these transcription factors depends on stimuli from cytokines, growth factors, and estrogens, among others. They appear to be relatively dispensable in normal mature cells, while they can be essential for the survival of certain cancers. Therefore, they have become excellent molecular targets for the discovery of new molecules that can be transformed into antitumor drugs. The overall objective of this project is to identify and characterize new chemical entities that are effective in treating diseases related to bromodominoes and proteins of the JAK-STAT oncogenic pathway.
Inhibition of glutamine metabolism as therapy against pancreatic ductal adenocarcinoma (METAPANC)
Reference: Agustín de Betancourt Project
Period: 01/27/2018 to 01/26/2022
IP: Miguel X. Fernandes
IP-ULL: José M. Padrón and Pablo Lorenzo
SUMMARYOver the past 40 years, while there have been significant advances in 5-year survival rates for most cancers, the 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has barely improved and remains close to the levels seen in 5%. PDAC cell metabolism changes in response to the oxygen-deprived and nutrient-poor environment. One of the most significant metabolic changes occurs in the glutamine pathway. In normal cells, glutamine would enter the tricarboxylic acid (TCA) cycle. However, in PDAC cells, glutamine is diverted to another pathway to generate NADPH, maintain cellular redox balance, and ensure proliferation. The enzymes in this glutamine pathway, reprogrammed by oncogenic KRAS, are GLS, GOT2, GOT1, MDH1, and ME1. This pathway is not used extensively by non-tumor cells. A dual inhibitor of GOT1 and GOT2 would significantly block glutamine metabolism in PDAC cells, suppressing tumor growth without affecting the viability of non-tumor cells. This small-molecule inhibitor, indicated for the treatment of PDAC, would be administered orally and would increase patient survival by at least 251 times compared to the standard of care for PDAC treatment.
The overall goal of the MetaPanc project is to demonstrate, in a preclinical setting, that dual inhibition, with small molecules, of GOT1 and GOT2, blocks PDAC growth.
Synthesis and characterization of new molecules as fluorescent probes with biomedical applications
Reference: Agustín de Betancourt Project
Period: 01/01/2019 to 12/31/2022
IP: Sandra Oramas Royo
IP-ULL: Ana Estévez Braun
SUMMARYThe use of fluorescent molecules with a molecular weight <500 is one of the most powerful tools currently available for visualizing biological processes in living cells and organisms in a selective and non-invasive manner. When these probes are incorporated into bioactive molecules, they enable the acquisition of selective and non-invasive images and insights of biologically relevant targets, thus allowing us to understand the biological processes in which these molecules are involved. In the last decade, the in vivo monitoring of tumors and other lesions with antibodies and peptides labeled with fluorescent molecules has attracted considerable attention.
The overall objective of this project is to develop new molecules that can serve as fluorescent probes or as temperature nanosensors in the physiological range. These new compounds can be patented and brought to market with the support of the participating company. Once the compounds are obtained, their photophysical properties will be measured in the laboratory of the "Laser Spectroscopy and High Pressures" group in the Physics Department of the Faculty of Sciences at the University of La Laguna (ULL).
Development of self-immolating “smart” anti-tumor prodrugs
Reference: Agustín de Betancourt Project
Period: 01/30/2020 to 01/29/2024
IP: Jimena Scoccia
IP-ULL: Víctor Sotero Martín García
SUMMARYOne of the major challenges in cancer treatment today is developing a drug that can act specifically where needed, increasing its effectiveness and minimizing side effects. Here we present prodrugs that exploit some of the subtle biochemical differences that characterize tumor cells to selectively activate the drug within them.
Synthesis of transfused oxacycles and evaluation against tuberculosis and Alzheimer's
Reference: Agustín de Betancourt Project
Period: 01/30/2020 to 01/29/2024
IP: Daniel Alejandro Cruz Perdomo
IP-ULL: Víctor Sotero Martín García
SUMMARYThe biodiversity of the marine environment, both animal and plant, generates a vast number of metabolites of great interest, as they possess structural and bioactivity patterns not readily found in terrestrial products. In this regard, cyclic structures again occupy a prominent place, appearing in all their forms. Regarding size, cyclic structures can range from three members, the smallest possible size, to macrocycles of nine or more members, encompassing all sizes of small (four and five members) and medium-sized (six, seven, and eight members) cycles. In terms of functionality, oxygenated heterocycles and lactones are the most common functional groups. Among all these possibilities, medium-sized oxacycles, and particularly transfused oxacycle groups, are a very prevalent structural motif in secondary metabolites of marine origin. Our research group has been working for several years on the idea of synthesizing transfused oxacyclic structures, with the aim of studying the relationships between structural complexity and the biological activities of these compounds. Thus, starting from a low level of complexity and using synthetic tools developed in the group, such as iron salt-catalyzed Prins cyclization, we have successfully synthesized several examples of transfused compounds with tetrahydropyran-tetrahydropyran and tetrahydropyran-oxepan structures. The main objective and interest lies in the generation of transfused oxacyclic compounds that possess therapeutic properties against diseases such as Alzheimer's and tuberculosis. To this end, we will increase the number of analogs for these systems. trans-fused tetrahydropyran-tetrahydropyran and tetrahydropyran-oxepan. In this regard, the different functional groups will be modified in order to modulate the pharmacokinetic and pharmacodynamic aspects. Once synthesized, their biological activities against Alzheimer's disease and tuberculosis will be tested. In addition, the effect of ring size changes will be explored, first by generating tetrahydrofuran-oxepan derivatives. Finally, attempts will be made to obtain more complex derivatives containing three oxacycles. trans-fused. After performing the various in vitro biological assays, the compounds that show the highest activity values will be selected to carry out the corresponding assays in vivo, which allow us to determine its therapeutic capacity.
Metabolomics and Chemometrics: efficient and effective tools for the biotechnological study of the chemical diversity of natural products of the marine microbiota
Reference: Agustín de Betancourt Project
Period: 01/30/2020 to 01/29/2024
IP: Nathália Nocchi
IP-ULL: José Javier Fernández
SUMMARYAmong the biodiversity found in the marine environment, microorganisms such as bacteria, cyanobacteria, yeasts, fungi, and microalgae—many still unknown—are fundamental to the functioning of the marine ecosystem and the maintenance of life. Moreover, these marine microorganisms represent a powerful resource for producing an impressive variety of unique structures with a wide range of biological activities, such as antimicrobial, antitumor, anti-inflammatory, and antiparasitic agents. This fact has attracted increasing attention from researchers aiming to identify new chemical entities as sources of novel compounds and their potential exploitation in the biotechnological field. This is particularly relevant to meeting the demand for medicines, as well as addressing ecological and environmental pollution problems. However, despite the growth in studies of the chemical diversity of natural products from the marine microbiota in recent years, this work is hampered by their low availability in the natural environment and the lengthy and tedious procedures for isolating and characterizing bioactive substances. Building on these previous foundations, this project proposes the development of a novel and appropriate analytical procedure for the qualitative and quantitative prediction of bioactive natural products and biotoxins from marine microorganisms. This approach will enable the predictive classification and search for bioactive compounds in complex mixtures by combining advanced, sophisticated metabolomics and chemometric analytical techniques for chemical and bioactivity data analysis. In parallel, we intend to develop a database of the chemical diversity of metabolites and a database of marine microbiota strains. Furthermore, a more detailed study of marine microorganisms with potential therapeutic and/or industrial applications will be conducted. This project is of great interest to the scientific and industrial community because it proposes strategies for linking chemical profiles and associated biological data in a fast, reliable, simple, inexpensive, and highly applicable manner. The challenges posed by the project require combining the generation of new knowledge with its application to technologies, products, and services that can contribute to Tenerife's scientific, technological, and business leadership in the future.
Projects of the ULL
The genus Hypericum, a source of chemical entities with potential pharmacological applications
Reference: 1192_2020
Period: 09/01/2020 to 08/31/2021
Funding received: €8,300
IP: Rodney Lacret Pimienta
SUMMARYHyperforin, the most abundant phloroglucinol within the Hypericum genus, has demonstrated a significant effect on some tumor cell lines. The results in vivo They demonstrated their ability to inhibit tumor growth comparable to that of paclitaxel. The results in vivo They demonstrated comparable tumor growth inhibition capabilities with paclitaxel. However, their poor solubility and stability in aqueous solutions limit the clinical potential of this compound. Therefore, species of the genus Hypericum may be a potentially interesting source of secondary metabolites with antiproliferative activity.
Of the species of this genus that grow in the Canary Islands, three of them (Canary Islander, H. grandifolium e H. reflexumThese four species have a clear history of antiproliferative activity, but to date, the antiproliferative activity of H. glandulosum has not been studied, nor have systematic and simultaneous studies of extracts from the four species been conducted against the same tumor cell lines. Furthermore, biodirected isolation, which would allow for the identification of the compounds responsible for the activity observed in the extracts, has not been performed.
The Hyperpharm project aims to understand the antiproliferative potential of species Canary Islander, H. glandulosum, H. grandifolium e H. reflexum as sources of chemical entities with potential pharmacological applications. To achieve this, the biological activity of polar extracts from the aerial parts of the aforementioned species will be evaluated against a panel of six human cell lines derived from solid tumors of diverse origins, and in a second stage, against immortalized non-tumor cell lines. This protocol will allow for the selection of the most promising species and the preparation of extracts from the selected species. These extracts will be subjected to the same panel of bioassays, enabling the selection of the most active extract. The most active extract will undergo bioguided fractionation using chromatographic techniques (VLC, Sephadex LH-20, and HPLC) to isolate the compounds responsible for the initially observed biological activity. Their structural elucidation will be established based on different spectroscopic methods: IR, UV, high-resolution mass spectrometry, and 1D and 2D NMR (HSQC, HMBC, COSY, NOESY). Finally, the biological activity of the isolated compounds will be evaluated.
The results of this project provide an important foundation and impetus for highly innovative Canary Island and European SMEs linked to the phytotherapy sector, as well as a greater understanding of the chemical and pharmacological potential of plant species that grow in the Canary archipelago.
Image labeling system based on a neural network for micromorphological description in archaeology
Reference: 1207_2020
Period: 09/01/2020 to 08/31/2021
Funding received: €8,300
IP: Rafael Arnay del Arco
Participating IUBO researchers: Carolina Mallol
SUMMARY: In the investigation of archaeological sediments, sediment samples are analyzed at a microscopic scale, among other things. In these samples, researchers identify different components and microstructures that provide information about the site from which they originate. The components tell us about the origin and nature of the archaeological deposit, which can be of anthropogenic, biological, geological, or a combination of these. They provide valuable clues about the human past, such as the function of a room, the vegetation present at the time of habitation, or food waste characteristic of the diet of the period. As for the microstructure, which basically consists of the sediment's porosity in relation to its spatial organization, it helps us identify processes (also anthropogenic, biological, geological, or a combination of these) that may have affected the sediment from the time it was deposited to the present day. Chemical alteration, removal by roots or worms, or human and animal traffic are examples of such processes. The porosity of sediment is usually limited to certain specific pore types: vesicles, channels, chambers, fissures, and cavities. Spatial organization typically occurs in the form of aggregates, granules, or prisms. The micromorphological classification of components and microstructures under a microscope is a slow process, which also involves a degree of subjectivity, as observations can be open to interpretation. This significantly slows down research and delays the acquisition of replicable information about the collected samples.
This project proposes the development of a machine learning system based on
Convolutional Neural Networks (Convolutional Neural Networks CNN), to address the task of classifying different types of structures in microscopic sediment images. This system will aid in labeling these images and in creating and expanding a database to help advance research in this field. Having such a database will allow for not only quantitative but also potentially qualitative improvements in the results. Quantitatively, the number of images that can be labeled, stored, and retrieved will increase thanks to this tool. Qualitatively, having a larger database and being able to share and integrate its information will improve the analysis and interpretation performed by researchers in this area.
Analysis of the overall response of multidrug-resistant strains of Staphylococcus aureus to subinhibitory concentrations of the antibiotic mupirocin
Reference: 1193_2020
Period: 09/01/2020 to 08/31/2021
Funding received: €8,300
IP: Guido Santos Rosales
Participating IUBO researchers: Eduardo Pérez Roth
SUMMARYThe discovery of penicillin in the mid-20th century radically changed the course of modern medicine. Most infections could now be treated successfully. Furthermore, many of the medical procedures performed today would not be possible without effective antibiotics: organ transplants, chemotherapy treatments, and surgical operations. However, for some decades now, the increasing resistance of bacteria to these drugs has been causing them to lose effectiveness at an alarming rate. Specifically, the emergence of infections caused by bacteria resistant to multiple antibiotics is especially worrying. Currently, there is no doubt that bacterial resistance to antibiotics is a global problem and one of the most serious health threats facing our society in the 21st century. Although much remains to be learned about the phenomenon of bacterial resistance, it seems clear that the main reason for its increase is the excessive and often inappropriate use of antibiotics. It is well known that the application of antibiotics leads to the generation of concentration gradients. In line with this, recent research has shown that non-lethal or sub-inhibitory concentrations of antibiotics have side effects on bacteria during treatment. These effects are diverse, ranging from the selection of resistant strains to modifications that affect the bacteria's pathogenic behavior.
In this project we intend to analyze the overall effect that sub-inhibitory concentrations of the antibiotic mupirocin have on the bacteria S. aureus. To do this, we will study the gene expression triggered in response to non-lethal doses of the antibiotic. S. aureus It is one of the pathogenic bacteria that causes the most deaths, especially due to its increasing acquisition of resistance to multiple antibiotics. Mupirocin is a particularly important antibiotic in controlling infections caused by it. S. aureus Multidrug-resistant bacteria. Currently, technology allows for the complete sequencing of all genes expressed by a bacterial culture in just a few minutes. Analyzing this data, we can identify genes that exhibit activation or repression in the presence of sub-inhibitory doses compared to untreated cells. The results of experimental analyses can be incorporated into mathematical models that simulate the transmission of the antibiotic response signal. This allows us to identify, among the most overexpressed molecules, those most sensitive to suppressing the signal transmitted by the molecular network. From the simulation results and sensitivity analysis, we can obtain a ranking of candidate genes for inhibition in bacteria exposed to sub-inhibitory doses of mupirocin. Validation of these genes can be performed by culturing the bacteria at sub-inhibitory doses with interfering RNA. This interfering RNA allows us to silence specific genes and compare the response to sub-inhibitory doses with cultures under control conditions. We expect to observe that the response produced by sub-inhibitory doses of antibiotics in bacteria is silenced when the bacteria are cultured in the presence of interfering RNAs.
Equipment Projects
Elemental analyzer attachable to an isotopic ratio mass spectrometer
Reference: EQC2019-005741-P
Period: 06/01/2019 to 05/31/2021
Financing granted: €209,315
IP: Carolina Mallol Duque
SUMMARY: This proposal requests an elemental analyzer with a "Gas bench" interface (gas test bench) that can be attached to an existing isotope ratio mass spectrometer (currently installed in the Micromorphology and Archaeological Biomarkers Laboratory at the University of La Laguna) for the determination of carbon (C), nitrogen (N), oxygen (O), hydrogen (H), and sulfur (S) in solid and/or liquid samples. This system is capable of determining C, N, and S in a single analysis for one sample (eliminating the need for repeated analyses to resolve the different elements). To achieve this, the system includes a simple reactor for the simultaneous determination of these elements, a second reactor for the simultaneous determination of hydrogen (H) and oxygen (O), a module for gradual heating of the chromatographic column, a module for reduced helium (He) consumption, an autosampler for liquids, and a thermostatically controlled sample tray. Furthermore, to ensure accurate quantification, an ultramicrobalance with its corresponding anti-vibration table must be acquired. This equipment will allow the requesting research groups (from fields as diverse as Archaeology, Geology, Materials Physics, and Marine Natural Product Analysis) to advance their current research projects. Specifically, it will enable them to obtain information about the diet and climate of past human societies, distinguish between biota sources, study the sulfur cycle in the environment, evaluate precipitation patterns, and characterize both synthetic and naturally derived materials. Furthermore, the requested equipment will benefit various studies by other research groups within the institution, as well as the research and industrial sectors of the islands. Several national and international researchers have also expressed interest in the equipment resulting from this acquisition.
Early pharmacological profile of marine natural products from Canary biodiversity (FARMACAN).
Reference: EIS 2020 06
Period: 01/01/2020 to 06/30/2021
Financing granted: €146,000
IP: José M. Padrón
SUMMARY: FARMACAN is an initiative aimed at enhancing our current offerings in knowledge generation and fostering excellence, with an emphasis on specialization and strengthening in the priority area of RIS3 biotechnology and biomedicine related to biodiversity. Simultaneously, FARMACAN contributes to promoting the sociocultural, economic, and environmentally sustainable development of our region. Sustainable development has been considered in FARMACAN's design as a competitive advantage compared to the lines of research pursued by other research groups in the same field. Furthermore, FARMACAN will strengthen the University of La Laguna by improving its scientific infrastructure, enabling it to achieve the objective of promoting R&D activities and the transfer of our results to the productive sector.
In general, FARMACAN's scientific objective is to strengthen our working model that combines experimental and computational data, to correlate phenotypic response patterns, anticipating the mechanism of action of new compounds with potential therapeutic application in the area of cancer.