Laura M. Sanz
A5067566321- Malaria Research and Control
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Mosquito-borne diseases and control
- Research on Leishmaniasis Studies
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- Synthesis and Catalytic Reactions
- Drug Transport and Resistance Mechanisms
- Protein purification and stability
- Synthesis and bioactivity of alkaloids
- Herpesvirus Infections and Treatments
- Hemoglobin structure and function
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- Tuberculosis Research and Epidemiology
- Neurological diseases and metabolism
- Blood groups and transfusion
- Quinazolinone synthesis and applications
- Blood properties and coagulation
- Hemoglobinopathies and Related Disorders
- Aquaculture disease management and microbiota
- Chemical Synthesis and Analysis
- Orthopedic Infections and Treatments
- Organoboron and organosilicon chemistry
GMV Innovating Solutions (Spain)
2025
GlaxoSmithKline (Spain)
2013-2023
GlaxoSmithKline (United Kingdom)
2014-2015
ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
MMV390048, a member of new class inhibitors the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.
Drug discovery for malaria has been transformed in the last 5 years by of many new lead compounds identified phenotypic screening. The process developing these as drug leads and studying cellular responses they induce is revealing targets that regulate key processes Plasmodium parasites cause malaria. We disclose herein clinical candidate (+)-SJ733 acts upon one targets, ATP4. ATP4 thought to be a cation-transporting ATPase responsible maintaining low intracellular Na(+) levels parasite....
Chemotherapy is still the cornerstone for malaria control. Developing drugs against Plasmodium parasites and monitoring their efficacy requires methods to accurately determine parasite killing rate in response treatment. Commonly used techniques essentially measure metabolic activity as a proxy viability. However, these approaches are susceptible artefacts, viability metabolism two parameters that coupled during life cycle but can be differentially affected drug actions. Moreover,...
To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has IC
Abstract Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 Plasmodium falciparum laboratory-adapted strains (mean IC 50 32 nM), Ugandan field isolates ex vivo 64 murine P. berghei infections (day 4 ED 90 0.34 0.57 mg kg −1 , respectively). Multiple lines selected in vitro for resistance to harboured point mutations pfcpsf3 which encodes a homologue mammalian cleavage polyadenylation specificity factor subunit...
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment malaria in particular, are high priority; however, there few chemically validated targets. The natural product cladosporin is active against blood- liver-stage Plasmodium falciparum Cryptosporidium parvum cell-culture studies. Target deconvolution P. has shown that inhibits lysyl-tRNA synthetase ( Pf KRS1). Here, we report identification a series...
Significance Protozoal proteasome is a validated target for antimalarial drug development, but species selectivity of reported inhibitors suboptimal. Here we identify with improved malaria β5 subunit over each active human proteasomes. These compounds kill the parasite in stage its life cycle. They interact synergistically β2 inhibitor and artemisinin. Resistance to arose through point mutation nonproteolytic β6 subunit. The same made mutant strain more sensitive less fit withstand...
Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors parasite lactate dehydrogenase (LDH), central to NAD+ regeneration, therefore potentially provide a route new antimalarial drugs directed against novel molecular target. A series heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar...
Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy endemic countries. Additionally, diversity chemical mode action global portfolio marketed antimalarials is extremely limited. Addressing urgent need for development new antimalarials, a class potent antimalarial compounds with novel was recently identified. Herein, preclinical characterization one these compounds, ACT-451840, conducted partnership academic and...
Abstract The widespread emergence of Plasmodium falciparum ( Pf ) strains resistant to frontline agents has fuelled the search for fast-acting with novel mechanism action. Here, we report discovery and optimization antimalarial compounds, triaminopyrimidines (TAPs), which emerged from a phenotypic screen against blood stages . clinical candidate (compound 12 is efficacious in mouse model malaria an ED 99 <30 mg kg −1 displays good vivo safety margins guinea pigs rats. With predicted...
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative identify develop potent preclinical candidates with distinct modes action. Here, we report the identification MMV688533, acylguanidine that was developed following a whole-cell screen compounds known hit high-value targets in human cells. MMV688533 displays fast parasite clearance vitro is not cross-resistant antimalarials. In P. NSG mouse model, long-lasting pharmacokinetic profile...
Abstract K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility artemisinin-based combination therapies, cornerstone modern day treatment. Here we describe multinational drug discovery programme has delivered synthetic tetraoxane-based molecule, E209, which meets key requirements Medicines for Malaria Venture candidate profiles. E209 potent nanomolar inhibitory activity against multiple strains P. and...
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate Compound 46 had excellent activity against cultured Plasmodium falciparum, P. falciparum berghei infected mice. It exhibited good PK properties mice, rats, dogs. was highly active other 11 strains, are...
The emergence of Plasmodium falciparum resistance to artemisinins threatens undermine the effectiveness artemisinin-based combination anti-malarial therapy. Developing suitable drugs replace requires identification new compounds that display rapid parasite killing kinetics. However, no current methods fully meet requirements screen large compound libraries for candidates with such properties. This study describes development and validation an in vitro viability fast assay identifying rapidly...
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties in vivo efficacy humanized mouse model Plasmodium falciparum infection. The compound shows single digit nanomolar vitro activity against P. vivax clinical isolates, potently blocks transmission Anopheles...
ABSTRACT Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for vivo efficacy pharmacokinetic properties prioritize direct compound development. TM2-115 displayed potent activity, 50% inhibitory concentrations (IC 50 s)...
Artemisinin derivatives and their partner drugs in artemisinin combination therapies (ACTs) have played a pivotal role global malaria mortality reduction during the last two decades. The loss of efficacy due to evolving drug-resistant parasites could become serious health threat. Dihydroartemisinin-piperaquine is well tolerated generally highly effective ACT. implementation drug ACTs critical control emerging resistance. Even though parasite clearance, it labile human body. A necessary for...
Abstract Aim To evaluate the safety, tolerability and pharmacokinetics in healthy participants of orally administered MMV367 (GSK3772701), a novel antimalarial interfering with Plasmodium falciparum acyl coenzyme A synthetase 10/11 function. Methods This first‐in‐human study enrolled 47 male female participants. Part 1 was randomised, double‐blind, placebo‐controlled which four sequential fasted cohorts received single ascending doses (100, 300, 750 1500 mg) or placebo (six active, two per...
From the phenotypic screening of AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against asexual blood stage Plasmodium falciparum (Pf). Medicinal chemistry optimization potency Pf and ADME properties resulted in identification 12 a lead molecule. Compound was efficacious P. berghei (Pb) model malaria. This displayed an excellent pharmacokinetic profile with long half-life (19 h) rat blood. led to extended survival animals for over 30 days...
The establishment of methods for an in vitro continuous culture Plasmodium falciparum is essential gaining knowledge into its biology and the development new treatments. Previously, several techniques have been used to synchronize, enrich concentrate P. falciparum, although obtaining cultures with high parasitaemia continues being a challenging process. Current produce levels synchronized by frequent changes medium or reducing haematocrit. However, these are time consuming sometimes lead...
A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure–activity relationship studies led to identification potent inhibitor 19f, 95-fold more than the original hit compound, active against laboratory-resistant strains malaria. Profiling 19f suggested fast in vitro killing profile. In vivo activity murine model human malaria dose-dependent manner constitutes concomitant benefit.