The main protease (Mpro) plays a major role in SARS-CoV-2 replication. Mpro cleaves the polyprotein to make multiple functional proteins or nonstructural proteins (nsps) that would come back together to make the replication transcription complex (RTC), which allows the virus to replicate itself. Thus, determining a structure for the polyprotein in complex with Mpro is a major area of interest in understanding the Mpro cleavage mechanism for developing more effective drugs against SARS-CoV-2.