Identification of an Antiretroviral Small Molecule That Appears To Be a Host-Targeting Inhibitor of HIV-1 Assembly.

ATP-Binding Cassette Transporters / metabolism Anti-Retroviral Agents / pharmacology DEAD-box RNA Helicases / metabolism HIV Infections / drug therapy HIV-1 / drug effects Humans Leukocytes, Mononuclear / drug effects Proto-Oncogene Proteins / metabolism Small Molecule Libraries / pharmacology Virus Assembly / drug effects gag Gene Products, Human Immunodeficiency Virus / metabolism
ABCE1 DDX6 HIV-1 assembly HIV-1 capsid RNA granules antiretroviral agent cell-free system drug screen virus-host interactions

Journal

Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724

Informations de publication

Date de publication:
13 01 2021
Historique:
received: 07 05 2020
accepted: 25 10 2020
pubmed: 6 11 2020
medline: 16 3 2021
entrez: 5 11 2020
Statut: epublish

Résumé

Given the projected increase in multidrug-resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life cycle stages not targeted by drugs currently in use. Host-targeting compounds are of particular interest because they can offer a high barrier to resistance. Here, we report identification of two related small molecules that inhibit HIV-1 late events, a part of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and peripheral blood mononuclear cells, and are effective against a primary isolate. They reduce virus production, likely by inhibiting a posttranslational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag

Identifiants

DOI: 10.1128/JVI.00883-20 PMID: 33148797 PMC: PMC7925099
pubmed: 33148797
pii: JVI.00883-20
doi: 10.1128/JVI.00883-20
pmc: PMC7925099
pii:
doi:

Substances chimiques

ABCE1 protein, human 0
ATP-Binding Cassette Transporters 0
Anti-Retroviral Agents 0
Proto-Oncogene Proteins 0
Small Molecule Libraries 0
gag Gene Products, Human Immunodeficiency Virus 0
DDX6 protein, human EC 3.6.1.-
DEAD-box RNA Helicases EC 3.6.4.13

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI150457
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI154963
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI145498
Pays : United States

Informations de copyright

Copyright © 2021 Reed et al.

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Auteurs

Jonathan C Reed (JC)

Department of Global Health, University of Washington, Seattle, Washington, USA.

Dennis Solas (D)

Prosetta Biosciences, San Francisco, California, USA.

Anatoliy Kitaygorodskyy (A)

Prosetta Biosciences, San Francisco, California, USA.

Beverly Freeman (B)

Prosetta Biosciences, San Francisco, California, USA.

Dylan T B Ressler (DTB)

Department of Global Health, University of Washington, Seattle, Washington, USA.

Daryl J Phuong (DJ)

Department of Global Health, University of Washington, Seattle, Washington, USA.

J Victor Swain (JV)

Department of Global Health, University of Washington, Seattle, Washington, USA.

Kent Matlack (K)

Prosetta Biosciences, San Francisco, California, USA.

Clarence R Hurt (CR)

Prosetta Biosciences, San Francisco, California, USA.

Vishwanath R Lingappa (VR)

Prosetta Biosciences, San Francisco, California, USA.

Jaisri R Lingappa (JR)

Department of Global Health, University of Washington, Seattle, Washington, USA jais@uw.edu.
ORCID: 0000-0002-7533-6276

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Transporteurs ABC › Identification of an Antiretroviral Small...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Antirétroviraux › Identification of an Antiretroviral Small...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › RNA helicases › DEAD-box RNA helicases › Identification of an Antiretroviral Small...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Infections à VIH › Identification of an Antiretroviral Small...
questionsmedicales.fr › Virus › Virus à ARN › Retroviridae › Lentivirus › Lentivirus des primates › VIH (Virus de l'Immunodéficience Humaine) › VIH-1 (Virus de l'Immunodéficience Humaine de type 1) › Identification of an Antiretroviral Small...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of an Antiretroviral Small...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Identification of an Antiretroviral Small...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Identification of an Antiretroviral Small...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › Identification of an Antiretroviral Small...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Assemblage viral › Identification of an Antiretroviral Small...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales structurales › Protéines nucléocapside › Protéines du core viral › Produits du gène gag › Produits du gène gag du virus de l'immunodéficience humaine › Identification of an Antiretroviral Small...