SARS‐CoV‐2 Spike Proteins: A Key Target for COVID‐19 Therapeutics Development

Abstract

The spike proteins that crown SARS‐CoV‐2, the novel coronavirus behind the nearly 2 million COVID‐19 deaths this year, may be the key to stopping the infectious disease firmly in its tracks. By recognizing and attaching to human cells, these spike proteins spearhead the process of SARS‐CoV‐2 infection in the body. Thus, understanding their architecture and mechanics is critical to pinpointing the vulnerabilities of this coronavirus and guiding therapeutic development. To that end, here we present a review of the latest discoveries in the spike proteins’ structure and function alongside a physical model of the spike protein, highlighting features of clinical interest in antibody, small‐molecule drug, and vaccine development. The spike protein is comprised of two functional domains. The outer S1 domain includes the receptor binding domain, which recognizes and binds to an angiotensin‐converting enzyme 2 (ACE2) receptor on the surface of a lung, heart, kidney, or intestinal cell. Then, facilitated by the highly flexible inner S2 domain, the spike protein folds in on itself and fuses the viral envelope with the plasma membrane of the human cell. In doing so, the spike protein opens the doors for SARS‐CoV‐2 to release its viral genome inside the cell. Because spike proteins are glycoproteins, meaning their ectodomain is covered with sugar chains, the virus can evade the detection of the immune system and spread quickly throughout vital organs The spike protein's position on the outer surface of SARS‐CoV‐2 and its critical role in the virus's function makes it one of the most promising targets for a coronavirus therapeutic. One novel approach to targeting spike proteins is the design of Anti‐S1 antibodies, which disarm the virus's ability to bind to the cell by attaching to the S1 subunit. The current challenge to antibody development is the flexibility of the S1 domain, which makes fusion highly effective. Further research is needed to stabilize the spike protein and maximize the efficacy of antibodies in inhibiting the virus's function. Another intriguing approach to coronavirus therapeutics is small‐molecule drug development. When linoleic acid (LA), an essential fatty acid molecule that maintains lung cell membranes, nestles into a newly discovered druggable pocket of the spike protein, the spike protein is locked into a less flexible, less infectious form. This new pocket is a putative binding site for even more potent small‐molecule inhibitors, which may be able to trap the spike protein in a completely non‐infectious form. With each new discovery surrounding the structure of the spike proteins at the heart of the COVID‐19 pandemic, we advance one step closer to developing novel therapeutics that trap SARS‐CoV‐2 in a virtually non‐infectious state.