Gregory L. Adams, Madeline G. Dans, Qingmiao Zhou, Wenyin Su, Anna Ngo, Kate E. Jarman, Maria V. Fawaz, Michael J. Kelly, III, John A. McCauley, David B. Olsen, Justin A. Boddey, Alan F. Cowman, Brad E. Sleebs
{"title":"Activity Refinement and Property Assessment of Peptidomimetics with Potent Antimalarial Activity That Target Plasmepsin V","authors":"Gregory L. Adams, Madeline G. Dans, Qingmiao Zhou, Wenyin Su, Anna Ngo, Kate E. Jarman, Maria V. Fawaz, Michael J. Kelly, III, John A. McCauley, David B. Olsen, Justin A. Boddey, Alan F. Cowman, Brad E. Sleebs","doi":"10.1021/acsinfecdis.6c00314","DOIUrl":null,"url":null,"abstract":"<p>Plasmepsin V is an essential aspartyl protease that cleaves\r\nthe <em>Plasmodium</em> export element in proteins targeted\r\nfor export\r\nfrom <em>Plasmodium</em> parasites into the host red blood\r\ncell. Substrate-mimicking peptidomimetics have been developed that\r\npotently inhibit plasmepsin V but show modest parasite activity. To\r\nadvance these inhibitors, we optimized their potency by introducing\r\na 2-chloro aryl group at P<sub>2</sub> and an <em>N</em>-terminal\r\nsulfonamide that yielded WM960, which showed markedly improved plasmepsin\r\nV inhibition while retaining high selectivity over plasmepsin IX and\r\nX and human aspartyl proteases. WM960 also demonstrated enhanced activity\r\nagainst asexual blood-stage parasites and effectively suppressed protein\r\nexport. However, WM960 displayed low metabolic stability and limited\r\nsystemic exposure in mice, highlighting the need to improve pharmacokinetic\r\nproperties in future development of peptidomimetic plasmepsin V targeted\r\nantimalarials.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"12 9","pages":"3114–3126"},"PeriodicalIF":4.5000,"publicationDate":"2026-09-11","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.6c00314","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/8/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Plasmepsin V is an essential aspartyl protease that cleaves
the Plasmodium export element in proteins targeted
for export
from Plasmodium parasites into the host red blood
cell. Substrate-mimicking peptidomimetics have been developed that
potently inhibit plasmepsin V but show modest parasite activity. To
advance these inhibitors, we optimized their potency by introducing
a 2-chloro aryl group at P2 and an N-terminal
sulfonamide that yielded WM960, which showed markedly improved plasmepsin
V inhibition while retaining high selectivity over plasmepsin IX and
X and human aspartyl proteases. WM960 also demonstrated enhanced activity
against asexual blood-stage parasites and effectively suppressed protein
export. However, WM960 displayed low metabolic stability and limited
systemic exposure in mice, highlighting the need to improve pharmacokinetic
properties in future development of peptidomimetic plasmepsin V targeted
antimalarials.
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.
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