Effect of a SARS-CoV-2 Protein Fragment on the Amyloidogenic Propensity of Human Islet Amyloid Polypeptide

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the onset of COVID-19 have been linked to an increased risk of developing type 2 diabetes. While a variety of mechanisms may ultimately be responsible for the onset of type 2 diabetes under these circumstances, one mechanism that has been postulated involves the increased aggregation of human islet amyloid polypeptide (hIAPP) through direct interaction with SARS-CoV-2 viral proteins. Previous computational studies investigating this possibility revealed that a nine-residue peptide fragment known as SK9 (SFYVYSRVK) from the SARS-CoV-2 envelope protein can stabilize the native conformation of hIAPP_1-37 by interacting with the N-terminal region of amylin. One of the areas particularly stabilized through this interaction encompasses residues 15-28 of amylin. Given these findings, we investigated whether SK9 could interact with short amyloidogenic sequences derived from this region of amylin. Here, we employ docking studies, molecular dynamics simulations, and biophysical techniques to provide theoretical as well as direct experimental evidence that SK9 can interact with hIAPP_12-18 and hIAPP_20-29 peptides. Furthermore, we demonstrate that SK9 not only can interact with these sequences but also serves to prevent the self-assembly of these amyloidogenic peptides. In striking contrast, we also show that SK9 has little effect on the amyloidogenic propensity of full-length amylin. These findings are contrary to previous published simulations involving SK9 and hIAPP_1-37. Such observations may assist in clarifying potential mechanisms of the SARS-CoV-2 interaction with hIAPP and its relevance to the onset of type 2 diabetes in the setting of COVID-19.