Design of a Metabolic Analog to Inhibit SARS-CoV-2 Cellular Entry

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 100,000,000 individuals and killed over 2,300,000 since it was first identified in December 2019. The virus’s mechanism of cellular entry is via attachment to the extracellular human angiotensin-converting-enzyme-2 (ACE-2) receptor with the viral spike (S) protein. A separate ganglioside-binding-domain on the viral S protein engages with sialic acids linked to extracellular ganglioside receptors. Using metabolic glycoengineering (MGE), a non-natural sialic acid precursor with varying chain length, bulkiness, or polarity can be incorporated into these ganglioside receptors; we hypothesize the non-natural gangliosides will obstruct S protein interactions, thus preventing cellular infection. Through the use of both in silico binding studies and in-vitro studies, we will determine the analog that best inhibits binding. Here, we investigate sialic acid-targeting analogs designed to prevent infection by the SARS-CoV-2 virus.