A5080340857- Malaria Research and Control
- Computational Drug Discovery Methods
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Mosquito-borne diseases and control
- Plant Virus Research Studies
- Synthesis and biological activity
- Synthesis and Biological Evaluation
- HIV Research and Treatment
- Parasitic Infections and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Synthesis and Catalytic Reactions
- Global Health and Surgery
- Viral gastroenteritis research and epidemiology
- HIV/AIDS drug development and treatment
- Insect Resistance and Genetics
- Parasites and Host Interactions
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Amoebic Infections and Treatments
- Infectious Diseases and Mycology
- vaccines and immunoinformatics approaches
- Escherichia coli research studies
GlaxoSmithKline (Spain)
2014-2024
GlaxoSmithKline (France)
2024
GlaxoSmithKline (United Kingdom)
2011-2022
GMV Innovating Solutions (Spain)
2021
Consejo Superior de Investigaciones Científicas
2007
Instituto de Química Médica
2004
Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes action. Since only 0.2-1% asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route interrupt disease transmission and mitigate selection. Here we present high-throughput screen gametogenesis against ~70,000 compound diversity library, identifying seventeen...
The development of new antimalarial compounds remains a pivotal part the strategy for malaria elimination. Recent large-scale phenotypic screens have provided wealth potential starting points hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared real time, anyone was able to participate, patents not sought. chemical subseries found exhibit oral activity but contained labile ester that could be replaced...
In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as activity, physicochemical properties, and dissimilarity to known structures, we have identified 47 optimization. Their are provided. We invite potential collaborators work with us discover new clinical candidates.
This Perspective discusses the published data and recent developments in research area of bromodomains parasitic protozoa. Further work is needed to evaluate tractability this target class context infectious diseases launch drug discovery campaigns identify develop antiparasite drugs that can offer differentiated mechanisms action.
Trypanosoma cruzi is a unicellular parasite that causes Chagas disease, which endemic in the American continent but also worldwide, distributed by migratory movements. A striking feature of trypanosomatids polycistronic transcription associated with post-transcriptional mechanisms regulate levels translatable mRNA. In this context, epigenetic regulatory have been revealed to be great importance, since they are only ones would control access RNA polymerases chromatin. Bromodomains protein...
One of the attractive properties artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, unique benefits these medicines are now compromised by prolonged parasite clearance times and increasing frequency treatment failures, attributed to increased tolerance Plasmodium falciparum artemisinin. This emerging artemisinin resistance threatens undermine effectiveness antimalarial combination therapies. Herein, we describe medicinal chemistry...
Abstract Leishmania are unicellular parasites that cause human and animal diseases. Like other kinetoplastids, they possess large transcriptional start regions (TSRs) which defined by histone variants lysine acetylation. Cellular interpretation of these chromatin marks is not well understood. Eight bromodomain factors, the reader modules for acetyl-lysine, found across genomes. Using L. mexicana , Cas9-driven gene deletions indicate BDF1–5 essential promastigotes. Dimerisable, split Cre...
The emergence of resistance to available antimalarials requires the urgent development new medicines. recent disclosure several thousand compounds active in vitro against erythrocyte stage Plasmodium falciparum has been a major breakthrough, though converting these hits into medicines challenges current strategies. A vivo screening concept was evaluated as strategy increase speed and efficiency drug discovery projects malaria. developed based on human disease parameters, i.e. parasitemia...
Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most with bromodomains part of nuclear complexes interact histone residues and regulate DNA replication, transcription, repair through chromatin structure remodeling. Bromodomain inhibitors small molecules the hydrophobic pocket bromodomains, interfering interaction histones. Using a fluorescent probe, we have developed an assay select bromodomain factor 2
Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered TCAMS through a variety criteria reported 47 series containing total 522 compounds. From this enhanced set, we identified carbamoyl triazole TCMDC-134379 (1), serine protease inhibitor, an excellent starting point for SAR...
New drugs that target
Malaria is still one of the most prevalent parasitic infections in world, with half world's population at risk for malaria. The effectiveness current antimalarial therapies, even that recent class drugs (artemisinin-combination ACTs), under continuous threat by spread resistant Plasmodium strains. As a consequence, there an urgent requirement new drugs. We previously reported identification 4(1H)-pyridones as novel series potent activities. low solubility was identified issue to address. In...
From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of most promising hits was TCMDC-139046, a molecule presenting an indoline core, which is well-known its anxiolytic properties interacting with serotonin antagonist receptors 5-HT2. The inhibition this target will complicate clinical development these compounds as antimalarials. Herein, present antimalarial profile series and our efforts to avoid...
Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes action, able relieve symptoms as fast the artemisinins and/or block transmission. During past few years, antimalarial community focused their...
Malaria continues to be a major global health problem, being particularly devastating in the African population under age of five. Artemisinin-based combination therapies (ACTs) are first-line treatment recommended by WHO treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As consequence, novel chemotypes urgently needed. Herein we report novel, vivo active, fast-acting antimalarial chemotype based on benzimidazole core. This discovery is...
Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans that affects skin, soft tissues, and bones, causing long-term morbidity, stigma, disability. The recommended treatment for BU requires 8 weeks of daily rifampicin clarithromycin together with wound care, physiotherapy, sometimes tissue grafting surgery. Recovery can take up to 1 year, it may pose an unbearable financial burden the household. Recent in vitro studies demonstrated beta-lactams combined are...
Antiparasitic oral drugs have been associated to lipophilic molecules due their intrinsic permeability. However, these kind of are numerous adverse effects, which extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we identified two small, soluble and simple hits that even presenting antiplasmodial activities in range 0.4–0.5 μM able show vivo activity.
Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus Leishmania. Current chemotherapies severely limited, and need for new antileishmanials is pressing international importance. Bromodomains epigenetic reader domains that have shown promising therapeutic potential cancer therapy may also present an attractive target to treat parasitic diseases. Here, we investigate Leishmania donovani bromodomain factor 5 (LdBDF5) as antileishmanial...
Since the appearance of resistance to current front-line antimalarial treatments, ACTs (artemisinin combination therapies), discovery novel chemical entities treat disease is recognized as a major global health priority. From GSK set, we identified an aminoxadiazole with antiparasitic profile comparable artemisinin (1), no cross-resistance in resistant strains panel and potential new mode action. A medicinal chemistry program allowed delivery compounds such 19 high solubility aqueous media,...
New drugs are critically needed to treat Cryptosporidium infections, particularly for malnourished children under 2 years old in the developing world and persons with immunodeficiencies. Bioactive compounds from Tres-Cantos GSK library that have activity against other pathogens were screened possible repurposing parvum growth. Nineteen grouped into nine structural clusters identified using an iterative process remove excessively toxic screen related library. Representatives of four different...
The protozoan parasite Cryptosporidium is a leading cause of diarrheal disease (cryptosporidiosis) and death in young children. Cryptosporidiosis can be life-threatening individuals with weak immunity such as HIV/AIDS patients organ transplant recipients. There currently no effective drug to treat cryptosporidiosis the pediatric immunocompromised population. Therefore, there an urgent need expedite discovery process order develop new therapies reduce global burden cryptosporidiosis. In this...
Abstract Leishmania are unicellular parasites that cause human and animal disease. Alongside other organisms in kinetoplastida, they have evolved an unusual genome architecture requires all RNA polymerase II transcribed genes to be expressed constitutively, with transcriptional start regions denoted by histone variants lysine acetylation. However, the way these chromatin marks interpreted cell is not understood. Seven predicted bromodomain factors (BDF1-7), reader modules for acetyl-lysine,...