Small-Molecule-Induced Protein Polymerization: Mechanisms and Therapeutic Implications.

Abstract

Small molecules that induce protein polymerization represent an emerging class of compounds with diverse therapeutic potential. This review provides a comprehensive overview of five such molecules: arsenic trioxide (As₂O₃), BI-3802, NVS-STG2, paclitaxel, and verteporfin. These compounds target different proteins (PML-RARα, BCL6, STING, β-tubulin, and p62, respectively) and exhibit varied mechanisms of action. Some, like As₂O₃ and BI-3802, induce polymerization leading to protein degradation, while others, such as NVS-STG2, activate protein function through polymerization. Paclitaxel, distinct from these, induces the stabilization of tubulin polymers. Verteporfin, on the other hand, uniquely causes covalent cross-linking of its target and other cellular proteins. This review explores the molecular mechanisms, structural insights, and therapeutic implications of these compounds, highlighting their potential in targeted protein degradation, cancer treatment, and modulation of cellular processes, such as autophagy and immune response. The diverse effects of these molecules underscore the complexity of protein polymerization in cellular function and disease, opening new avenues for drug discovery and development.