Natalie Fuchs, Robert A. Zimmermann, Marvin Schwickert, Annika Gunkel, Collin Zimmer, Mergim Meta, Kevin Schwickert, Jennifer Keiser, Cécile Haeberli, Werner Kiefer and Tanja Schirmeister*,
{"title":"针对曼氏血吸虫设计新药的双重策略:改进表型和 SmCB1 抑制剂以提高疗效","authors":"Natalie Fuchs, Robert A. Zimmermann, Marvin Schwickert, Annika Gunkel, Collin Zimmer, Mergim Meta, Kevin Schwickert, Jennifer Keiser, Cécile Haeberli, Werner Kiefer and Tanja Schirmeister*, ","doi":"10.1021/acsinfecdis.4c00020","DOIUrl":null,"url":null,"abstract":"<p >In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm <i>Schistosoma mansoni</i> and its target protease <i>S. mansoni</i> cathepsin B1 (<i>Sm</i>CB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds’ in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in <i>S. mansoni</i> newly transformed schistosomula (NTS), adult worms, and <i>Sm</i>CB1 inhibition. The optimized compounds from both approaches (“phenotypic” vs “<i>Sm</i>CB1” approach) demonstrated improved efficacy against <i>S. mansoni</i> NTS and adult worms, with <b>2h</b> from the “<i>Sm</i>CB1” approach emerging as the most potent compound. <b>2h</b> displayed nanomolar inhibition of <i>Sm</i>CB1 (<i>K</i><sub>i</sub> = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound <b>2h</b> toward <i>S. mansoni</i> adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dual Strategy to Design New Agents Targeting Schistosoma mansoni: Advancing Phenotypic and SmCB1 Inhibitors for Improved Efficacy\",\"authors\":\"Natalie Fuchs, Robert A. Zimmermann, Marvin Schwickert, Annika Gunkel, Collin Zimmer, Mergim Meta, Kevin Schwickert, Jennifer Keiser, Cécile Haeberli, Werner Kiefer and Tanja Schirmeister*, \",\"doi\":\"10.1021/acsinfecdis.4c00020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm <i>Schistosoma mansoni</i> and its target protease <i>S. mansoni</i> cathepsin B1 (<i>Sm</i>CB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds’ in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in <i>S. mansoni</i> newly transformed schistosomula (NTS), adult worms, and <i>Sm</i>CB1 inhibition. The optimized compounds from both approaches (“phenotypic” vs “<i>Sm</i>CB1” approach) demonstrated improved efficacy against <i>S. mansoni</i> NTS and adult worms, with <b>2h</b> from the “<i>Sm</i>CB1” approach emerging as the most potent compound. <b>2h</b> displayed nanomolar inhibition of <i>Sm</i>CB1 (<i>K</i><sub>i</sub> = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound <b>2h</b> toward <i>S. mansoni</i> adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.</p>\",\"PeriodicalId\":17,\"journal\":{\"name\":\"ACS Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-04-30\",\"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.4c00020\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00020","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Dual Strategy to Design New Agents Targeting Schistosoma mansoni: Advancing Phenotypic and SmCB1 Inhibitors for Improved Efficacy
In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm Schistosoma mansoni and its target protease S. mansoni cathepsin B1 (SmCB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds’ in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in S. mansoni newly transformed schistosomula (NTS), adult worms, and SmCB1 inhibition. The optimized compounds from both approaches (“phenotypic” vs “SmCB1” approach) demonstrated improved efficacy against S. mansoni NTS and adult worms, with 2h from the “SmCB1” approach emerging as the most potent compound. 2h displayed nanomolar inhibition of SmCB1 (Ki = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound 2h toward S. mansoni adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.
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.