A5052321084- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Malaria Research and Control
- Circular RNAs in diseases
- Computational Drug Discovery Methods
- HIV/AIDS drug development and treatment
- Cancer-related molecular mechanisms research
- Mosquito-borne diseases and control
- RNA and protein synthesis mechanisms
- Neurological diseases and metabolism
- Biochemical and Molecular Research
- Cancer Genomics and Diagnostics
- Research on Leishmaniasis Studies
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- HIV Research and Treatment
- Inflammasome and immune disorders
- Epigenetics and DNA Methylation
- Trypanosoma species research and implications
- Chemical Synthesis and Analysis
- Vitamin K Research Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Parasites and Host Interactions
- Invertebrate Immune Response Mechanisms
Memorial Sloan Kettering Cancer Center
2022-2025
Columbia University Irving Medical Center
2021-2024
The APOBEC3 family of cytosine deaminases has been implicated in some the most prevalent mutational signatures cancer1-3. However, a causal link between endogenous enzymes and human cancer genomes not established, leaving mechanisms mutagenesis poorly understood. Here, to investigate mutagenesis, we deleted genes from cell lines that naturally generate APOBEC3-associated over time4. Analysis non-clustered clustered across whole-genome sequences 251 breast, bladder lymphoma line clones...
The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the R561H mutation Rwanda and highlights continuing dominance wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y M579I, confer elevated vitro ART some African strains, contrasting minimal changes susceptibility others. M579I cause substantial...
We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 MMV084978) selects for mutations in PfAcAS. Metabolic profiling compound-treated parasites reveals changes acetyl-CoA levels both compounds. Genome editing confirms that PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate is essential asexual...
Chromosomal instability is a hallmark of human cancer that associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking cGAS-STING immune response through the accumulation cytosolic DNA. The mechanisms how tumors benefit from chromosomal while mitigating risks, such as enhanced surveillance, are poorly understood. Here, we identify cGAS-STING-dependent upregulation nuclease TREX1 an adaptive, negative feedback mechanism...
APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations over 50% of cancers. mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact on cancer progression, understanding its contribution susceptibility malignant transformation is limited. We examine existing for role carcinogenesis basis reported associations between germline polymorphisms genes encoding enzymes risk, insights...
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential use in prophylaxis, which represents an unmet need malaria drug discovery portfolio endemic countries, particularly areas high transmission Africa. We describe structure-based computationally driven lead optimization program pyrrole-based series inhibitors,...
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...
Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development functional liver merozoites (prophylactic activity), blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization binding scaffold discovery potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation safety evaluation early characterization precluded compounds long human half-life (t1/2)...
Extrachromosomal DNA (ecDNA) are circular bodies that play critical roles in tumor progression and treatment resistance by amplifying oncogenes across a wide range of cancer types. ecDNA lack centromeres thus not constrained typical Mendelian segregation, enabling their unequal accumulation within daughter cells associated increases copy number. Despite intrinsic links to oncogenic potential, the fidelity mechanisms inheritance poorly understood. Here, we show protected against cytosolic...
Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected susceptible to breakage, phenomenon known as replication catastrophe. However, the mechanism by which breaks remains unclear. Here, we reveal APOBEC3B is key enzyme targeting at forks, initiating reaction cascade induces fork collapse poly(ADP-ribose) polymerase 1 (PARP1)...
We report an analysis of the propensity antimalarial agent cabamiquine, a Plasmodium-specific eukaryotic elongation factor 2 inhibitor, to select for resistant Plasmodium falciparum parasites. Through in vitro studies laboratory strains and clinical isolates, humanized mouse model, volunteer infection studies, we identified resistance-associated mutations at 11 amino acid positions. Of these, six (55%) were present more than one indicating translatability across models. Mathematical...
Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of set PRS ATP-site binders, initially designed for human indications, led to identification 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing novel scaffold. Evidence designates cytoplasmic as the drug The frontrunner 1 and its active enantiomer 1-S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains development liver schizonts. No...
Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified novel tetrazole-based series that shows fast-kill kinetics relatively low propensity develop high-level Preliminary structure-activity relationships were established including identification of subseries related amides with antiplasmodial activity. Assaying parasites resistance antimalarials led us test whether the had similar mechanism action...
<div>Abstract<p>Chromosomal instability is a hallmark of human cancer that associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking cGAS-STING immune response through the accumulation cytosolic DNA. The mechanisms how tumors benefit from chromosomal while mitigating risks, such as enhanced surveillance, are poorly understood. Here, we identify cGAS-STING–dependent upregulation nuclease TREX1 an adaptive,...
<p>Characterization of intratumoral immune cell infiltration.</p>
<p>Frequency of micronucleation and micronuclear envelope rupture are similar across KO models.</p>
<p>Generation of KO cell lines and extracellular cGAMP measurements.</p>
<p>Characterization of intratumoral immune cell infiltration.</p>
<p>Individual growth curves of tumors treated with anti-PD-1 and isotype controls.</p>
<p>Individual growth curves of tumors transplanted in Rag1 KO and NU/J hosts.</p>
<p>Individual growth curves of tumors treated with anti-PD-1 and isotype controls.</p>
<p>Paclitaxel treatment increases micronucleation, cGAS activity, and TREX1 expression.</p>
<p>IFN and gene expression analysis after treatment with paclitaxel, HT-DNA, poly(I:C).</p>
<p>TREX1 promotes tumor growth, but not in vitro cell proliferation.</p>
<p>Paclitaxel treatment increases micronucleation, cGAS activity, and TREX1 expression.</p>