Viral proteinases: targets of opportunity

Abstract

During antiviral drug development, any essential stage of the viral life cycle can serve as a potential drug target. Since most viruses encode specific proteases whose cleavage activity is required for viral replication, and whose structure and activity are unique to the virus and not the host cell, these enzymes make excellent targets for drug development. Success using this approach has been demonstrated with the plethora of protease inhibitors approved for use against HIV. This discussion is designed to review the field of antiviral drug development, focusing on the search for protease inhibitors, while highlighting some of the challenges encountered along the way. Protease inhibitor drug discovery efforts highlighting progress made with HIV, HCV, HRV, and vaccinia virus as a model system are included. Drug Dev. Res.

Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

“…However, others see bacterial, viral, and parasitic diseases as a golden opportunity for irreversible inhibitor design, in part because the drug is only administered for a short period of time, thereby reducing any off-target toxicity . Viral proteases have been recognized as excellent drug targets because they are essential for the virus to replicate and provide an opportunity for specificity by their exogenous origins, and their mechanism-based inhibitors are believed to be less susceptible to resistance, since they target the catalytically essential residues. , Transition state analogues such as saquinavir are anti-HIV protease drugs . A covalently acting SARS coronavirus 3CL protease inhibitor has also shown promising efficacy …”

“…70 Viral proteases have been recognized as excellent drug targets because they are essential for the virus to replicate and provide an opportunity for specificity by their exogenous origins, and their mechanism-based inhibitors are believed to be less susceptible to resistance, since they target the catalytically essential residues. 84,85 Transition state analogues such as saquinavir are anti-HIV protease drugs. 58 A covalently acting SARS coronavirus 3CL protease inhibitor has also shown promising efficacy.…”

A quantum-dot based protein module for in vivo monitoring of protease activity through fluorescence resonance energy transfer

“…Because of their importance in disease progression and viral infection, [1][2][3][4][5] proteases have become a prime target for drug therapy. 6,7 Cell-based high-throughput screening assays, by which compounds that most effectively inhibit the targeted protease can be identified, are needed as they provide information on both the transport efficiency and the adverse effects of the drug targets.…”

Papaverine, a promising therapeutic agent for the treatment of COVID‐19 patients with underlying cardiovascular diseases (CVDs)

“…These virus‐induced cellular lesions are called cytopathic effects (CPE). Bioactive compounds that can inhibit the CPE of viruses have valuable potential for clinical applications (Byrd & Hruby, 2006 ). This effect can occur through the effects of CPE inhibitors through both direct effects on viral targets and regulation of host‐dependent factors.…”