دورية أكاديمية
أعرض في EDS

Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation.

التفاصيل البيبلوغرافية
العنوان: Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation.
المؤلفون: Shi H; Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Suite 523 Bridgeside Point II, 450 Technology Drive , Pittsburgh , Pennsylvania 15219 , United States., Tice CM; Fox Chase Chemical Diversity Center, Inc. , Pennsylvania Biotechnology Center , 3805 Old Easton Road , Doylestown , Pennsylvania 18902 , United States., Emert-Sedlak L; Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Suite 523 Bridgeside Point II, 450 Technology Drive , Pittsburgh , Pennsylvania 15219 , United States., Chen L; Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Suite 523 Bridgeside Point II, 450 Technology Drive , Pittsburgh , Pennsylvania 15219 , United States., Li WF; Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Suite 523 Bridgeside Point II, 450 Technology Drive , Pittsburgh , Pennsylvania 15219 , United States., Carlsen M; Fox Chase Chemical Diversity Center, Inc. , Pennsylvania Biotechnology Center , 3805 Old Easton Road , Doylestown , Pennsylvania 18902 , United States., Wrobel JE; Fox Chase Chemical Diversity Center, Inc. , Pennsylvania Biotechnology Center , 3805 Old Easton Road , Doylestown , Pennsylvania 18902 , United States., Reitz AB; Fox Chase Chemical Diversity Center, Inc. , Pennsylvania Biotechnology Center , 3805 Old Easton Road , Doylestown , Pennsylvania 18902 , United States., Smithgall TE; Department of Microbiology and Molecular Genetics , University of Pittsburgh School of Medicine , Suite 523 Bridgeside Point II, 450 Technology Drive , Pittsburgh , Pennsylvania 15219 , United States.
المصدر: ACS infectious diseases [ACS Infect Dis] 2020 Feb 14; Vol. 6 (2), pp. 302-312. Date of Electronic Publication: 2019 Dec 16.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : ACS Publications, [2015]-
مواضيع طبية MeSH: Anti-Retroviral Agents/*pharmacology , Histocompatibility Antigens Class I/*genetics , Pyrazoles/*pharmacology , Virus Replication/*drug effects , nef Gene Products, Human Immunodeficiency Virus/*antagonists & inhibitors, Cell Line ; Down-Regulation ; Drug Development ; HIV-1/drug effects ; HIV-1/physiology ; Humans ; Inhibitory Concentration 50 ; Leukocytes, Mononuclear/virology ; Tissue Donors
مستخلص: The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo and promotes immune escape of infected cells via downregulation of cell-surface MHC-I. Previously, we discovered small molecules that bind directly to Nef and block many of its functions, including enhancement of viral infectivity and replication in T cell lines. These compounds also restore cell-surface MHC-I expression in HIV-infected CD4 T cells from AIDS patients, enabling recognition and killing by autologous cytotoxic T lymphocytes (CTLs). In this study, we describe the synthesis and evaluation of a diverse set of analogs based on the original hydroxypyrazole Nef inhibitor core. All analogs were screened for the interaction with recombinant HIV-1 Nef by surface plasmon resonance (SPR) and for antiretroviral activity in TZM-bl reporter cells infected with HIV-1. Active analogs were ranked on the basis of an activity score that integrates three aspects of the SPR data (affinity, residence time, and extent of binding) with antiretroviral activity. The top scoring compounds bound tightly to Nef by SPR, with K D values in the low nM to pM range, and displayed very slow dissociation from their Nef target. These analogs also suppressed HIV-1 replication in donor peripheral blood mononuclear cells (PBMCs) with IC 50 values in the 1-10 nM range without cytotoxicity, inhibited Nef-mediated IL-2-inducible tyrosine kinase (Itk) and hematopoietic cell kinase (Hck) activation, and rescued MHC-I downregulation in a Nef-transfected T cell line. The development of Nef inhibitors based on the structure-activity relationships defined here has promise as a new approach to antiretroviral therapy that includes a path to eradication of HIV-infected cells via the adaptive immune response.
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معلومات مُعتمدة: R01 AI057083 United States AI NIAID NIH HHS; R41 GM112516 United States GM NIGMS NIH HHS; R42 GM112516 United States GM NIGMS NIH HHS; R01 AI152677 United States AI NIAID NIH HHS; UM1 AI126617 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: HIV accessory proteins; HIV-1 Nef inhibitors; HIV/AIDS; antiretroviral drug development; surface plasmon resonance
المشرفين على المادة: 0 (Anti-Retroviral Agents)
0 (Histocompatibility Antigens Class I)
0 (Pyrazoles)
0 (nef Gene Products, Human Immunodeficiency Virus)
0 (nef protein, Human immunodeficiency virus 1)
تواريخ الأحداث: Date Created: 20191129 Date Completed: 20210111 Latest Revision: 20210526
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8142392
DOI: 10.1021/acsinfecdis.9b00382
PMID: 31775511
قاعدة البيانات: MEDLINE
الوصف
تدمد:2373-8227
DOI:10.1021/acsinfecdis.9b00382