{"title":"Identification of a De Novo Peptide against Palmitoyl Acyltransferase 6 to Block Survivability and Infectivity of Leishmania donovani","authors":"Pallavi Srivastava, Ruby Bansal, Evanka Madan, Rumaisha Shoaib, Jhalak Singhal, Amandeep Kaur Kahlon, Aashima Gupta, Swati Garg, Anand Ranganathan* and Shailja Singh*, ","doi":"10.1021/acsinfecdis.4c00063","DOIUrl":null,"url":null,"abstract":"<p >Palmitoylation is an essential post-translational modification in <i>Leishmania donovani</i>, catalyzed by enzymes called palmitoyl acyl transferases (PATs) and has an essential role in virulence. Due to the toxicity and promiscuity of known PAT inhibitors, identification of new molecules is needed. Herein, we identified a specific novel <i>de novo</i> peptide inhibitor, PS1, against the PAT6 <i>Leishmania donovani</i> palmitoyl acyl transferase (<i>Ld</i>PAT6). To demonstrate specific inhibition of <i>Ld</i>PAT6 by PS1, we employed a bacterial orthologue system and metabolic labeling-coupled click chemistry where both <i>Ld</i>PAT6 and PS1 were coexpressed and displayed palmitoylation suppression. Furthermore, strong binding of the <i>Ld</i>PAT6-DHHC domain with PS1 was observed through analysis using microscale thermophoresis, ELISA, and dot blot assay. PS1 specific to <i>Ld</i>PAT6 showed significant growth inhibition in promastigotes and amastigotes by expressing low cytokines levels and invasion. This study reveals discovery of a novel <i>de novo</i> peptide against <i>Ld</i>PAT6-DHHC which has potential to block survivability and infectivity of <i>L. donovani</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00063","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Palmitoylation is an essential post-translational modification in Leishmania donovani, catalyzed by enzymes called palmitoyl acyl transferases (PATs) and has an essential role in virulence. Due to the toxicity and promiscuity of known PAT inhibitors, identification of new molecules is needed. Herein, we identified a specific novel de novo peptide inhibitor, PS1, against the PAT6 Leishmania donovani palmitoyl acyl transferase (LdPAT6). To demonstrate specific inhibition of LdPAT6 by PS1, we employed a bacterial orthologue system and metabolic labeling-coupled click chemistry where both LdPAT6 and PS1 were coexpressed and displayed palmitoylation suppression. Furthermore, strong binding of the LdPAT6-DHHC domain with PS1 was observed through analysis using microscale thermophoresis, ELISA, and dot blot assay. PS1 specific to LdPAT6 showed significant growth inhibition in promastigotes and amastigotes by expressing low cytokines levels and invasion. This study reveals discovery of a novel de novo peptide against LdPAT6-DHHC which has potential to block survivability and infectivity of L. donovani.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.