Structural Impact of Mutation D614G in SARS-CoV‑2 Spike Protein: Enhanced Infectivity and Therapeutic Opportunity

• Published in: ACS Medicinal Chemistry Letters Vol. 11; no. 9; pp. 1667 - 1670
• Main Author: Fernández, Ariel
• Format: Journal Article Web Resource
• Language: English
• Published: Washington American Chemical Society 10.09.2020
• Subjects: Viewpoint
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.0c00410

With the COVID-19 pandemic, the evolutionary fate of SARS-CoV-2 becomes a matter of utmost concern. Mutation D614G in the spike (S) protein has become dominant, and recent evidence suggests it yields a more stable phenotype with higher transmission efficacy. We carry out a structural analysis that provides mechanistic clues on the enhanced infectivity. The D614G substitution creates a sticky packing defect in subunit S1, promoting its association with subunit S2 as a means to stabilize the structure of S1 within the S1/S2 complex. The results raise the therapeutic possibility of immunologically targeting the epitope involved in stabilizing the G614 phenotype as a means of reducing the infection efficacy of SARS-CoV-2. This therapeutic modality would not a-priori interfere directly with current efforts toward the immunological targeting of the RBD epitope; hence, it could be exploited as a complementary treatment.