Scalable Inhibitors of the Nsp3–Nsp4 Coupling in SARS-CoV-2
Abdul‐Rahman Azizogli, Varun Pai, Francesco Coppola, Roya Jafari, Joseph Dodd‐o, Rohan Harish, Bhavani Balasubramanian, Jatin Kashyap, Amanda M. Acevedo‐Jake, Petr Král, Vivek Kumar · ACS Omega · 2023
profiles), maintain fixed-Nsp4-ligand complexes in molecular dynamics (MD) simulations, and tightly associate with Nsp4 via hydrophobic interactions. Additionally, alternative peptide inhibitors based on Nsp3 were designed and shown in MD simulations to provide a highly stable binding to the Nsp4 protein. Finally, these therapeutics were attached to dendrimer structures to promote their multivalent binding with Nsp4, especially its large flexible luminal loop (Nsp4LLL). The therapeutics tested in this study represent many different approaches for targeting large flexible protein structures, especially those localized to the ER. This study is the first work targeting the membrane rearrangement system of viruses and will serve as a potential avenue for treating viruses with similar replicative function.