Challenges for developing selective viral protease inhibitors as antiinfectives

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Viral proteases are critical components of viral replication and have emerged as significant targets for antiviral drug development.
• While effective protease inhibitors (PIs) exist for HIV, HCV, and SARS-CoV-2, many other viruses encoding proteases are now under investigation.
• These include enteroviruses, filoviruses (Zika, Dengue), togaviruses, and hemorrhagic fever viruses, with their proteases being cloned and characterized.

Purpose of the Study:

• To review the current landscape of viral proteases as drug targets.
• To discuss the challenges and innovative strategies in designing novel protease inhibitors (PIs).
• To highlight the potential of PIs against a broader range of viral infections.

Main Methods:

• Review of existing literature on viral proteases and antiviral drug development.
• Analysis of challenges in designing peptidomimetic and non-peptidomimetic PIs.
• Discussion of strategies to overcome issues like selectivity, pharmacokinetics, and drug resistance.

Main Results:

• Over 25 PIs are clinically available for HIV, HCV, and SARS-CoV-2.
• Proteases from numerous other significant viral pathogens have been identified, cloned, and characterized.
• No PIs targeting these emerging viral threats have reached clinical trials yet.

Conclusions:

• Developing novel PIs faces hurdles including complex drug design, selectivity, in vivo efficacy, and resistance.
• Innovative strategies are being explored to address these challenges in antiviral drug discovery.
• Targeting viral proteases remains a promising avenue for combating a wide spectrum of viral diseases.