Inhibiting HTLV-1 Protease: A Viable Antiviral Target.

Autor:	Lockbaum GJ; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Henes M; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Talledge N; Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, Minnesota 55455, United States., Rusere LN; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Kosovrasti K; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Nalivaika EA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Somasundaran M; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Ali A; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Mansky LM; Institute for Molecular Virology, Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, Minnesota 55455, United States., Kurt Yilmaz N; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States., Schiffer CA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2021 Mar 19; Vol. 16 (3), pp. 529-538. Date of Electronic Publication: 2021 Feb 23.
DOI:	10.1021/acschembio.0c00975
Abstrakt:	Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that can cause severe paralytic neurologic disease and immune disorders as well as cancer. An estimated 20 million people worldwide are infected with HTLV-1, with prevalence reaching 30% in some parts of the world. In stark contrast to HIV-1, no direct acting antivirals (DAAs) exist against HTLV-1. The aspartyl protease of HTLV-1 is a dimer similar to that of HIV-1 and processes the viral polyprotein to permit viral maturation. We report that the FDA-approved HIV-1 protease inhibitor darunavir (DRV) inhibits the enzyme with 0.8 μM potency and provides a scaffold for drug design against HTLV-1. Analogs of DRV that we designed and synthesized achieved submicromolar inhibition against HTLV-1 protease and inhibited Gag processing in viral maturation assays and in a chronically HTLV-1 infected cell line. Cocrystal structures of these inhibitors with HTLV-1 protease highlight opportunities for future inhibitor design. Our results show promise toward developing highly potent HTLV-1 protease inhibitors as therapeutic agents against HTLV-1 infections.
Databáze:	MEDLINE
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