Shifting paradigms: The promise of allosteric inhibitors against dengue virus protease

Dengue, a mosquito-borne viral infection caused by the dengue virus (DENV), is a global health challenge. Annually, approximately 400 million cases are reported worldwide, signaling a persistent upward trend from previous years and projected a manifold increase in the future. There is a growing need for innovative and integrated approaches aimed at effective disease management. In this regard, scientific efforts are underway to find a new antiviral inhibitor that is desperately needed due to the growing prevalence of dengue, along with inadequate vector control and few vaccinations. The NS2B-NS3 protease complex within the DENV genome holds significant importance, making it an attractive target for potential interventions. Many competitive inhibitors are not clinically relevant even after extensive study, and these early hits are often not followed up to viable leads. The current focus is on exploring alternative target sites for developing effective anti-dengue compounds, resulting in the identification of various allosteric sites in recent years. While previous reviews have extensively covered active site inhibitors, this is to the best of our knowledge the first comprehensive review discussing the allosteric sites and allosteric inhibitors in greater detail. The present survey may assist researchers in understanding the key aspects and identifying new antagonists targeting the allosteric site of DENV protease.