ORCID Profile
0000-0002-4810-9334
Current Organisation
University of California, San Diego
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-03-2023
DOI: 10.1126/SCITRANSLMED.ADC9249
Abstract: Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multistage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan–life cycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.
Publisher: Cold Spring Harbor Laboratory
Date: 23-11-2022
DOI: 10.1101/2022.11.22.517223
Abstract: Changes in host cell morphology and transcription after apicomplexan parasite infection have long been noted, but there have been few studies of the functional consequences of host cell remodeling. Here we show, using time-dependent immunofluorescence microscopy of multiple human cell lines (HepG2, HC-04, Huh7.5.1 and primary human hepatocytes), infected with multiple Plasmodium species ( Plasmodium berghei, P. falciparum and P. vivax (hypnozoites and schizonts)), and antibodies to multiple human proteins (HsNR4A3, HsMUC13, HsGOLGA8A, HsCGA, HsBiP, HsCXCL2), that human protein trafficking is extensively modified in Plasmodium infected cells. Using conventional as well as ultrastructure expansion microscopy we show that newly-synthesized human proteins are trafficked to the parasitophorous vacuole instead of the infected-cell plasma membrane, nucleus or extracellular space. Universal redirection of human signaling proteins cells the parasitophorous vacuole may provide a mechanistic explanation for how apicomplexan parasites can block host cells response to infection.
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2022
DOI: 10.1101/2022.10.16.512381
Abstract: Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified ( S )-SW228703 (( S )-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to ( S )-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus ( Pf CARL) and P. falciparum acetyl CoA transporter ( Pf ACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of ( S )-SW703 is shared with some reported Pf CARL-associated compounds however, we observed that strict S-stereochemistry was required for activity of ( S )-SW703, suggesting differences in mechanism of action or binding mode. ( S )-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-10-2022
DOI: 10.1126/SCITRANSLMED.ABO7219
Abstract: Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human "mammalian target of rapamycin" (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and in vivo asexual blood stage (ABS) activity, and transmission-blocking activity against the protozoan parasite
Location: United States of America
No related grants have been discovered for nimisha mittal.