Targeting conserved dynamic regions of SARS-CoV-2 spike protein identified by normal mode analysis for broad-spectrum antiviral therapy

Abstract

The continuous emergence of SARS-CoV-2 variants challenges conventional antiviral strategies that targets highly mutable epitopes or enzymatic active sites. We propose a novel hypothesis centered on targeting the conserved dynamic regions of the SARS-CoV-2 spike (S) glycoprotein, which govern its large-scale conformational transitions. Through normal mode analysis (NMA), these regions have been identified as critical dynamic hotspots that facilitate an allosteric transition from the closed to the open, ACE2-accessible state. We hypothesize that small molecules or peptides designed to bind these hotspots could act as conformational locks, thereby providing broad-spectrum antiviral activity. The feasibility of targeting the physical dynamics of the spike protein is supported by independent studies on its mechanical vulnerability. While identifying druggable allosteric pockets and achieving experimental validation still need be overcome before practical realization, this strategy represents a paradigm shift from static, structure-based targeting to dynamic allostery. It offers a potentially variant-resilient therapeutic approach against both current and future threats from coronaviruses.