Comparative Pharmacology of Caspase-1 Inhibitors: Ac-YVAD-CMK, Z-YVAD-FMK, and Ac-YVAD-CHO in Multisystem Diseases

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Caspase-1 is a key target in inflammatory diseases and pyroptosis.
• Existing peptide inhibitors (Ac-YVAD-CMK, Z-YVAD-FMK, Ac-YVAD-CHO) are foundational but have limitations.
• Systematic medicinal chemistry reassessment is needed to optimize these scaffolds.

Purpose of the Study:

• To rigorously interrogate archetypal Caspase-1 inhibitor scaffolds.
• To define structure-kinetics-pharmacology relationships for inhibitor design.
• To identify barriers and outline pathways for clinical translation of Caspase-1 inhibitors.

Main Methods:

• Systematic review integrating evidence from 144 studies (2015-2025).
• Analysis of C-terminal warhead chemistry and N-terminal capping strategies.
• Correlation of chemical architecture with selectivity, off-target engagement, and in vivo efficacy.

Main Results:

• Warhead chemistry dictates inhibitor covalency, reversibility, and selectivity.
• N-terminal capping influences membrane permeability, metabolic stability, and exposure.
• Barriers to clinical translation include poor pharmacokinetics, metabolic instability, and cross-reactivity.

Conclusions:

• Legacy peptide inhibitors can serve as templates for optimization.
• Design principles include kinetic selectivity, warhead refinement, and context-guided optimization.
• Strategic pathways are outlined for developing selective, clinically viable Caspase-1 therapeutics.