ACS Infectious Diseases最新文献

{"title":"Building Spatiotemporal Understanding of Mycobacterium tuberculosis-Host Interactions","authors":"Anna-Lisa E. Lawrence,&nbsp; and ,&nbsp;Shumin Tan*,&nbsp;","doi":"10.1021/acsinfecdis.4c0084010.1021/acsinfecdis.4c00840","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00840https://doi.org/10.1021/acsinfecdis.4c00840","url":null,"abstract":"<p >Heterogeneity during <i>Mycobacterium tuberculosis</i> (Mtb) infection greatly impacts disease outcome and complicates treatment. This heterogeneity encompasses many facets, spanning local differences in the host immune response to Mtb and the environment experienced by the bacterium, to nonuniformity in Mtb replication state. All of these facets are interlinked and each can affect Mtb susceptibility to antibiotic treatment. In-depth spatiotemporal understanding of Mtb-host interactions is thus critical to both fundamental comprehension of Mtb infection biology and for the development of effective therapeutic regimens. Such spatiotemporal understanding dictates the need for analysis at the single bacterium/cell level in the context of intact tissue architecture, which has been a significant technical challenge. Excitingly, innovations in spatial single cell methodology have opened the door to such studies, beginning to illuminate aspects ranging from intergranuloma differences in cellular composition and phenotype, to sublocation differences in Mtb physiology and replication state. In this perspective, we discuss recent studies that demonstrate the potential of these methodological advancements to reveal critical spatiotemporal insight into Mtb-host interactions, and highlight future avenues of research made possible by these advances.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"277–286 277–286"},"PeriodicalIF":4.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small and Versatile Cyclotides as Anti-infective Agents","authors":"Elizabete de Souza Cândido,&nbsp;Liryel Silva Gasparetto,&nbsp;Livia Veiga Luchi,&nbsp;João Pedro Farias Pimentel,&nbsp;Marlon Henrique Cardoso,&nbsp;Maria Lígia Rodrigues Macedo,&nbsp;Cesar de la Fuente-Nunez* and Octávio Luiz Franco*,&nbsp;","doi":"10.1021/acsinfecdis.4c0095710.1021/acsinfecdis.4c00957","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00957https://doi.org/10.1021/acsinfecdis.4c00957","url":null,"abstract":"<p >Plants provide an abundant source of potential therapeutic agents, including a diverse array of compounds, such as cyclotides, which are peptides known for their antimicrobial activity. Cyclotides are multifaceted molecules with a wide range of biological activities. Their unique topology forms a head-to-tail cyclic structure reinforced by a cysteine knot, which confers chemical and thermal stability. These molecules can directly target membranes of infectious agents by binding to phosphatidylethanolamine in lipid membranes, leading to membrane permeabilization. Additionally, they function as carriers and cell-penetrating molecules, demonstrating antiviral, antibacterial, antifungal, and nematicidal properties. The structure of cyclotides is also amenable to chemical synthesis, facilitating drug design through residue substitutions or grafting of bioactive epitopes within the cyclotide scaffold to enhance peptide stability. In this review, we explore the multifunctionality of these biomolecules as anti-infective agents, emphasizing their potential as a novel class of antimicrobial drugs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"386–397 386–397"},"PeriodicalIF":4.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00957","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections","authors":"Victoria Banas,&nbsp;Mostafa A. Elfawal,&nbsp;Bruce A. Rosa,&nbsp;Matthew Mahoney,&nbsp;Jacquelyn Kauffman,&nbsp;Emily Goetz,&nbsp;Paulina Chen,&nbsp;Raffi V. Aroian*,&nbsp;Makedonka Mitreva* and James W. Janetka*,&nbsp;","doi":"10.1021/acsinfecdis.4c0086410.1021/acsinfecdis.4c00864","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00864https://doi.org/10.1021/acsinfecdis.4c00864","url":null,"abstract":"<p >Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human and animal health, with limited treatment options and emerging drug resistance. <i>Trichuris trichiura</i> (whipworm) stands out as a neglected disease, necessitating new drugs to address this unmet medical need. We discovered that several different chemical series of related human Provirus Integration sites for Moloney murine leukemia virus (PIM) family kinase inhibitors possess potent anthelmintic activity by using whole-worm motility assays. Systematic structure–activity relationship (SAR) studies based on the <i>pan</i>-PIM kinase inhibitor CX-6258 were conducted to identify compounds displaying improved <i>in vitro</i> motility inhibition of both adult hookworm (<i>Ancylostoma ceylanicum</i>) and adult whipworm (<i>Trichuris muris</i>) nematodes. A broad kinase selectivity screen of &gt;450 human kinases confirms PIM1 kinase and others as potential targets for CX-6258 and analogues thereof. In addition, we demonstrated that CX-6258 significantly reduced worm burden and egg counts in the <i>T. muris</i> infection model of mice, establishing it as a new oral small molecule anthelmintic therapeutic.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"506–517 506–517"},"PeriodicalIF":4.0,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional Mycobacterial Topoisomerases with Distinctive Features","authors":"Iqball Faheem,&nbsp; and ,&nbsp;Valakunja Nagaraja*,&nbsp;","doi":"10.1021/acsinfecdis.4c0088010.1021/acsinfecdis.4c00880","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00880https://doi.org/10.1021/acsinfecdis.4c00880","url":null,"abstract":"<p >Tuberculosis (TB) continues to be a major cause of death worldwide despite having an effective combinatorial therapeutic regimen and vaccine. Being one of the most successful human pathogens, <i>Mycobacterium tuberculosis</i> retains the ability to adapt to diverse intracellular and extracellular environments encountered by it during infection, persistence, and transmission. Designing and developing new therapeutic strategies to counter the emergence of multidrug-resistant and extensively drug-resistant TB remains a major task. DNA topoisomerases make up a unique class of ubiquitous enzymes that ensure steady-state level supercoiling and solve topological problems occurring during DNA transactions in cells. They continue to be attractive targets for the discovery of novel classes of antibacterials and to develop better molecules from existing drugs by virtue of their reaction mechanism. The limited repertoire of topoisomerases in <i>M. tuberculosis</i>, key differences in their properties compared to topoisomerases from other bacteria, their essentiality for the pathogen’s survival, and validation as candidates for drug discovery provide an opportunity to exploit them in drug discovery efforts. The present review provides insights into their organization, structure, function, and regulation to further efforts in targeting them for new inhibitor discovery. First, the structure and biochemical properties of DNA gyrase and Topoisomerase I (TopoI) of mycobacteria are described compared to the well-studied counterparts from other bacteria. Next, we provide an overview of known inhibitors of DNA gyrase and emerging novel bacterial topoisomerase inhibitors (NBTIs). We also provide an update on TopoI-specific compounds, highlighting mycobacteria-specific inhibitors.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"366–385 366–385"},"PeriodicalIF":4.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential of Mycobacterium tuberculosis Type II NADH-Dehydrogenase in Antitubercular Drug Discovery","authors":"Pallavi Saha,&nbsp;Mohit Kumar and Deepak K. Sharma*,&nbsp;","doi":"10.1021/acsinfecdis.4c0100510.1021/acsinfecdis.4c01005","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01005https://doi.org/10.1021/acsinfecdis.4c01005","url":null,"abstract":"<p >The type II NADH-dehydrogenase enzyme in <i>Mycobacterium tuberculosis</i> plays a critical role in the efficient functioning of the oxidative phosphorylation pathway. It acts as the entry point for electrons in the electron transport chain, which is essential for fulfilling the energy requirements of both replicating and nonreplicating mycobacterial species. Due to the absence of the type II NADH-dehydrogenase enzyme in mammalian mitochondria, targeting the type II NADH-dehydrogenase enzyme for antitubercular drug discovery could be a vigilant approach. Utilizing type II NADH-dehydrogenase inhibitors in antitubercular therapy led to bactericidal response, even in monotherapy. However, the absence of the cryo-EM structure of <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase has constrained drug discovery efforts to rely on high-throughput screening methods, limiting the use of structure-based drug discovery. Here, we have delineated the literature-reported <i>Mycobacterium tuberculosis</i> type II NADH-dehydrogenase inhibitors and the rationale behind selecting this specific enzyme for antitubercular drug discovery, along with shedding light on the architecture of the enzyme structure and functionality. The gap in the current research and future research direction for TB treatment have been addressed.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"398–412 398–412"},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Synthetic Peptides from Schistosoma mansoni ATP Diphosphohydrolase 1: In Silico Approaches for Characterization and Prospective Application in Diagnosis of Schistosomiasis","authors":"Danielle Gomes Marconato,&nbsp;Beatriz Paiva Nogueira,&nbsp;Vinícius Carius de Souza,&nbsp;Rafaella Fortini Grenfell e Queiroz,&nbsp;Clovis R. Nakaie,&nbsp;Eveline Gomes Vasconcelos and Priscila de Faria Pinto*,&nbsp;","doi":"10.1021/acsinfecdis.4c0069710.1021/acsinfecdis.4c00697","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00697https://doi.org/10.1021/acsinfecdis.4c00697","url":null,"abstract":"<p >Schistosomiasis is the infection caused by <i>Schistosoma mansoni</i> and constitutes a worldwide public health problem. The parasitological recommended method and serological methods can be used for the detection of eggs and antibodies, respectively. However, both have limitations, especially in low endemicity areas. Thus, new approaches for the diagnosis of schistosomiasis are essential. In this study, a six-amino acid peptide and derived sequences from SmATPDase1 were synthesized for the evaluation of immunogenicity. SmATPDase1 is included in a protein group in <i>S. mansoni</i> tegument; therefore, its peptides could be potential candidates for diagnostic antigens. In the hypothetical SmATPDase1 three-dimensional structure, peptides are located in a region exposed and accessible to antibody binding. In addition, peptide amino acid sequences are conserved in the most relevant <i>Schistosoma</i> species and have low identity with human NTPDases isoforms. Swiss mice immunization resulted in significant anti-peptide polyclonal antibodies production, which recognized a 63 kDa protein in tegument and adult worm preparations. By immunofluorescence microscopy, polyclonal antibodies also identified this enzyme in cercariae. Sera of infected animals presented high seropositivity in ELISA-peptides, with an area under curve (AUC) greater than 0.96 for all peptides. In mice with low parasite burden, we observed a seropositivity AUC &gt; 0.9. Reactivity in the prepatent period exhibited AUC values greater than 0.94 for all peptides. Anti-P1425 monoclonal antibodies were successfully produced, and mAbs recognized the integral protein in ELISA and Western blots. The data indicate that peptides from SmATPDase1 are potential biomarkers for schistosomiasis, and anti-peptide antibodies are interesting tools for the detection of the infection.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"463–473 463–473"},"PeriodicalIF":4.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c00697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereospecific Resistance to N2-Acyl Tetrahydro-β-carboline Antimalarials Is Mediated by a PfMDR1 Mutation That Confers Collateral Drug Sensitivity","authors":"Emily K. Bremers,&nbsp;Joshua H. Butler,&nbsp;Leticia S. Do Amaral,&nbsp;Emilio F. Merino,&nbsp;Hanan Almolhim,&nbsp;Bo Zhou,&nbsp;Rodrigo P. Baptista,&nbsp;Maxim Totrov,&nbsp;Paul R. Carlier and Maria Belen Cassera*,&nbsp;","doi":"10.1021/acsinfecdis.4c0100110.1021/acsinfecdis.4c01001","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c01001https://doi.org/10.1021/acsinfecdis.4c01001","url":null,"abstract":"<p >Half the world’s population is at risk of developing a malaria infection, which is caused by parasites of the genus <i>Plasmodium</i>. Currently, resistance has been identified to all clinically available antimalarials, highlighting an urgent need to develop novel compounds and better understand common mechanisms of resistance. We previously identified a novel tetrahydro-β-carboline compound, PRC1590, which potently kills the malaria parasite. To better understand its mechanism of action, we selected for and characterized resistance to PRC1590 in <i>Plasmodium falciparum</i>. Through <i>in vitro</i> selection of resistance to PRC1590, we have identified that a single-nucleotide polymorphism on the parasite’s multidrug resistance protein 1 (PfMDR1 G293V) mediates resistance to PRC1590. This mutation results in stereospecific resistance and sensitizes parasites to other antimalarials, such as mefloquine, quinine, and MMV019017. Intraerythrocytic asexual stage specificity assays have revealed that PRC1590 is most potent during the trophozoite stage when the parasite forms a single digestive vacuole (DV) and actively digests hemoglobin. Moreover, fluorescence microscopy revealed that PRC1590 disrupts the function of the DV, indicating a potential molecular target associated with this organelle. Our findings mark a significant step in understanding the mechanism of resistance and the mode of action of this emerging class of antimalarials. In addition, our results suggest a potential link between resistance mediated by PfMDR1 and PRC1590’s molecular target. This research underscores the pressing need for future research aimed at investigating the intricate relationship between a compound’s chemical scaffold, molecular target, and resistance mutations associated with PfMDR1.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"529–542 529–542"},"PeriodicalIF":4.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsinfecdis.4c01001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unfolding the Potential of Pyrrole- and Indole-Based Allylidene Hydrazine Carboximidamides as Antimicrobial Agents","authors":"Amit Sharma,&nbsp;Sonali J. Jain,&nbsp;Prabhat Nath Jha,&nbsp;Santosh Rudrawar,&nbsp;Sandip B. Bharate and Hemant R. Jadhav*,&nbsp;","doi":"10.1021/acsinfecdis.4c0084910.1021/acsinfecdis.4c00849","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00849https://doi.org/10.1021/acsinfecdis.4c00849","url":null,"abstract":"<p >Antimicrobial drug resistance is a significant global health challenge, causing hundreds of thousands of deaths annually and severely impacting healthcare systems worldwide. Several reported antimicrobial compounds have a guanidine motif, as the positive charge on guanidine promotes cell lysis. Therefore, pyrrole- and indole-based allylidene hydrazine carboximidamide derivatives with guanidine motifs are proposed as antimicrobial agents that mimic cationic antimicrobial peptides (CAMPs). A total of 72 derivatives having pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide and indol-3-yl-phenyl allylidene hydrazine carboximidamide scaffolds were assessed for their inhibitory potential against a panel of Gram-positive and Gram-negative bacteria. Analogs <b>1j</b>, <b>1k</b>, <b>1s</b>, <b>2j</b>, <b>2q</b>, <b>4a</b>, <b>4c</b>, <b>4h</b>, <b>5b</b>, <b>6a</b>, and <b>6d</b> exhibited potent broad-spectrum antimicrobial activity better than the standard antibiotics. Also, these compounds showed no cytotoxicity up to 3-fold of the minimum inhibitory concentration, and structure–activity relationship was established. Further, the most active compound, <b>6a</b>, showed a strong biofilm disruption, acted on the bacterial membrane, and lysed it. The further development of these compounds as novel antimicrobial agents is warranted.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"11 2","pages":"493–505 493–505"},"PeriodicalIF":4.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic <i>Plasmodium berghei</i>.","authors":"Isabella Ramella Gal, Claudia Demarta-Gatsi, Diana Fontinha, Francisca Arez, Sebastian G Wicha, Matthias Rottmann, Helena Nunes-Cabaço, Johanne Blais, Jay Prakash Jain, Suresh B Lakshminarayana, Catarina Brito, Miguel Prudêncio, Paula M Alves, Thomas Spangenberg","doi":"10.1021/acsinfecdis.4c00563","DOIUrl":"10.1021/acsinfecdis.4c00563","url":null,"abstract":"<p><p>New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of <i>Plasmodium</i> drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of <i>Plasmodium</i> infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with <i>in vitro-in silico</i> checkerboard analysis. The <i>in vitro</i> study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent <i>P. berghei</i> parasites. The <i>in vivo</i> efficacy of this drug combination was assessed against the liver stage of the <i>P. berghei</i>. Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma C_av0-24/EC₅₀ ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of <i>Plasmodium</i> infection and prevent the development of parasitemia.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"69-79"},"PeriodicalIF":4.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice.","authors":"Olawale S Adeyinka, Michael D Barrera, Damilohun S Metibemu, Niloufar Boghdeh, Carol A Anderson, Haseebullah Baha, Olamide Crown, John Adeolu Falode, Janard L Bleach, Amanda R Bliss, Tamia P Hampton, Jane-Frances Chinenye Ojobor, Farhang Alem, Aarthi Narayanan, Ifedayo Victor Ogungbe","doi":"10.1021/acsinfecdis.4c00701","DOIUrl":"10.1021/acsinfecdis.4c00701","url":null,"abstract":"<p><p>New World alphaviruses, including Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that cause disease in humans. These viruses are endemic to the western hemisphere, and disease in humans may lead to encephalitis and long-term neurological sequelae. There are currently no FDA-approved vaccines or antiviral therapeutics available for the prevention or treatment of diseases caused by these viruses. The alphavirus nonstructural protein 2 (nsP2) functions as a protease, which is critical for the establishment of a productive viral infection by enabling accurate processing of the nsP123 polyprotein. Owing to the essential role played by nsP2 in the alphavirus infectious process, it is also a valuable therapeutic target. In this article, we report the synthesis and evaluation of novel small molecule inhibitors that target the alphavirus nsP2 protease via a covalent mode of action. The two lead compounds demonstrated robust inhibition of viral replication <i>in vitro</i>. These inhibitors interfered with the processing of the nsP123 polyprotein as determined using VEEV TC-83 as a model pathogen and are active against EEEV and WEEV. The compounds were found to be nontoxic in two different mouse strains and demonstrated antiviral activity in a VEEV TC-83 lethal challenge mouse model. Cumulatively, the outcomes of this study provide a compelling rationale for the preclinical development of nsP2 protease inhibitors as direct-acting antiviral therapeutics against alphaviruses.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":"181-196"},"PeriodicalIF":4.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}