Viral proteases: Structure, mechanism and inhibition

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab

Publication Date


Document Type

Book Chapter


Biochemistry, Biophysics, and Structural Biology | Enzymes and Coenzymes | Infectious Disease | Virology | Virus Diseases | Viruses


Viral proteases are diverse in structure, oligomeric state, catalytic mechanism, and substrate specificity. This chapter focuses on proteases from viruses that are relevant to human health: human immunodeficiency virus subtype 1 (HIV-1), hepatitis C (HCV), human T-cell leukemia virus type 1 (HTLV-1), flaviviruses, enteroviruses, and coronaviruses. The proteases of HIV-1 and HCV have been successfully targeted for therapeutics, with picomolar FDA-approved drugs currently used in the clinic. The proteases of HTLV-1 and the other virus families remain emerging therapeutic targets at different stages of the drug development process. This chapter provides an overview of the current knowledge on viral protease structure, mechanism, substrate recognition, and inhibition. Particular focus is placed on recent advances in understanding the molecular basis of diverse substrate recognition and resistance, which is essential toward designing novel protease inhibitors as antivirals.


Coronavirus, Drug resistance, Enterovirus, Flavivirus, HCV, HIV-1, HTLV-1, Protease inhibitors, Substrate envelope, Viral protease

DOI of Published Version



Zephyr J, Kurt Yilmaz N, Schiffer CA. Viral proteases: Structure, mechanism and inhibition. Enzymes. 2021;50:301-333. doi: 10.1016/bs.enz.2021.09.004. Epub 2021 Nov 17. PMID: 34861941; PMCID: PMC8595904. Link to article on publisher's site

Journal/Book/Conference Title

The Enzymes

Related Resources

Link to Article in PubMed

PubMed ID