Author
Rini Chaturvedi
Bio: Rini Chaturvedi is an academic researcher from International Centre for Genetic Engineering and Biotechnology. The author has contributed to research in topics: Malaria & Plasmodium falciparum. The author has an hindex of 3, co-authored 7 publications receiving 42 citations.
Topics: Malaria, Plasmodium falciparum, Medicine, Plasmodium vivax, DHPS
Papers
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TL;DR: This review establishes a platform for systematic experimental dissection of malarial parasite aaRSs as a new focus for sustained drug development efforts against malaria.
43 citations
TL;DR: In this article, the authors provide an overview of the geographical spread of SP resistance mutations in Plasmodium falciparum (Pf) encoded dhps and dhfr genes and map the mutation data to the three-dimensional structures of DHPS and DHFR which have become available.
13 citations
11 citations
TL;DR: The PvHPPK–DHPS structure rationalizes and unravels the structural bases for SDX resistance mutations and highlights architectural features in HPPK– DHPSs from malaria parasites that can form the basis for developing next-generation anti-folate agents to combat malaria parasites.
11 citations
TL;DR: This is the first account of country-wide assimilation of reported malaria parasite species data that covers Pm, Po, and Pk infection profiles from 1930 to 2020 and illustrates the need to survey all 5 human malaria parasitespecies in India and to target them collectively during the malaria elimination phase.
10 citations
Cited by
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University of Dundee1, University of Washington2, University of Georgia3, Imperial College London4, Medicines for Malaria Venture5, University of Vermont6, Scripps Health7, Swiss Tropical and Public Health Institute8, University of Basel9, GlaxoSmithKline10, International Centre for Genetic Engineering and Biotechnology11, Pasteur Institute12, University of California, San Diego13, Seattle Children's Research Institute14, University of Toronto15, University of Pennsylvania16, McGill University Health Centre17
TL;DR: This work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis and identifies an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS.
Abstract: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
74 citations
University of Pretoria1, University of Cape Town2, University of California, San Diego3, Council for Scientific and Industrial Research4, National Health Laboratory Service5, University of the Witwatersrand6, Washington University in St. Louis7, Pennsylvania State University8, GlaxoSmithKline9, Medicines for Malaria Venture10, South African Medical Research Council11
TL;DR: In this article, the authors report the parallel de novo screening of the MMV Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides.
Abstract: Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages. Here, Reader et al. screen the Medicines for Malaria Venture Pandemic Response Box in parallel against Plasmodiumasexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. They identify two potent transmission-blocking drugs: a histone demethylase inhibitor ML324 and the antitubercular SQ109.
51 citations
TL;DR: The infection and immune responses induced by pathogen ARSs, as well as the potential anti-infective compounds that target pathogenARSs are addressed, and the functional mechanisms of ARss in the development of immune cells are described.
Abstract: Aminoacyl-tRNA synthetases (ARSs) play a vital role in protein synthesis by linking amino acids to their cognate transfer RNAs (tRNAs). This typical function has been well recognized over the past few decades. However, accumulating evidence reveals that ARSs are involved in a wide range of physiological and pathological processes apart from translation. Strikingly, certain ARSs are closely related to different types of immune responses. In this review, we address the infection and immune responses induced by pathogen ARSs, as well as the potential anti-infective compounds that target pathogen ARSs. Meanwhile, we describe the functional mechanisms of ARSs in the development of immune cells. In addition, we focus on the roles of ARSs in certain immune diseases, such as autoimmune diseases, infectious diseases, and tumor immunity. Although our knowledge of ARSs in the immunological context is still in its infancy, research in this field may provide new ideas for the treatment of immune-related diseases.
43 citations
TL;DR: It is shown that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS), and this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.
Abstract: The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.
37 citations
TL;DR: The parallel screening of the Medicines for Malaria Venture Pandemic Response Box to identify multistage-active and stage-specific compounds against various life cycle stages of Plasmodium parasites identified four structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity.
Abstract: New chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel screening of the Medicines for Malaria Venture Pandemic Response Box to identify multistage-active and stage-specific compounds against various life cycle stages of Plasmodium parasites (asexual parasites, stage IV/V gametocytes, gametes, oocysts and liver stages) and for endectocidal activity. Hits displayed unique chemotypes and included two multistage-active compounds, 16 asexual-targeted, six with prophylactic potential and ten gametocyte-targeted compounds. Notably, four structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity were identified: the JmjC inhibitor ML324, two azole antifungals including eberconazole, and the antitubercular clinical candidate SQ109. Besides ML324, none of these have previously attributed antiplasmodial activity, emphasizing the success of de novo parallel screening against different Plasmodium stages to deliver leads with novel modes-of-action. Importantly, the discovery of such transmission-blocking targeted compounds covers a previously unexplored base for delivery of compounds required for malaria elimination strategies.
36 citations