دورية أكاديمية
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TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform.

التفاصيل البيبلوغرافية
العنوان: TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform.
المؤلفون: Peiffer AL; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48019, United States.; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States., Garlick JM; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48019, United States.; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Wu Y; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Wotring JW; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States., Arora S; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Harmata AS; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Bochar DA; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Stephenson CJ; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Soellner MB; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Sexton JZ; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.; University of Michigan Medical School, Ann Arbor, Michigan 48109, United States., Brooks CL 3rd; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Biophysics, University of Michigan, Ann Arbor, Michigan 48109, United States., Mapp AK; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48019, United States.; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
المصدر: ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 May 30; Vol. 14 (6), pp. 860-866. Date of Electronic Publication: 2023 May 30 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society
مستخلص: The COVID-19 pandemic has highlighted the need for new antiviral approaches because many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a promising antiviral target because it plays a role in priming the spike protein before viral entry occurs for the most virulent variants. Further, TMPRSS2 has no established physiological role, thereby increasing its attractiveness as a target for antiviral agents. Here, we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we identify new noncovalent TMPRSS2 inhibitors that block SARS-CoV-2 infectivity in a cellular model. One such inhibitor, debrisoquine, has high ligand efficiency, and an initial structure-activity relationship study demonstrates that debrisoquine is a tractable hit compound for TMPRSS2.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
التعليقات: Update of: bioRxiv. 2021 Mar 27:2021.03.22.436465. doi: 10.1101/2021.03.22.436465. (PMID: 33791707)
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معلومات مُعتمدة: P30 CA046592 United States CA NCI NIH HHS; R35 GM130587 United States GM NIGMS NIH HHS; R35 GM136356 United States GM NIGMS NIH HHS
تواريخ الأحداث: Date Created: 20230607 Latest Revision: 20240729
رمز التحديث: 20240729
مُعرف محوري في PubMed: PMC10237299
DOI: 10.1021/acsmedchemlett.3c00035
PMID: 37284689
قاعدة البيانات: MEDLINE
الوصف
تدمد:1948-5875
DOI:10.1021/acsmedchemlett.3c00035