University of Massachusetts Medical School Faculty Publications

Title

Inhibiting HTLV-1 Protease: A Viable Antiviral Target

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab

Publication Date

2021-02-23

Document Type

Article

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal-Pharmaceutical Chemistry | Pharmaceutics and Drug Design | Structural Biology | Virus Diseases | Viruses

Abstract

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 muM 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.

Keywords

Infectious diseases, Peptides and proteins, Crystal structure, Inhibitors, Crystal cleavage

DOI of Published Version

10.1021/acschembio.0c00975

Source

Lockbaum GJ, Henes M, Talledge N, Rusere LN, Kosovrasti K, Nalivaika EA, Somasundaran M, Ali A, Mansky LM, Kurt Yilmaz N, Schiffer CA. Inhibiting HTLV-1 Protease: A Viable Antiviral Target. ACS Chem Biol. 2021 Feb 23. doi: 10.1021/acschembio.0c00975. Epub ahead of print. PMID: 33619959. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

ACS chemical biology

PubMed ID

33619959

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