The SARS-CoV-2 main protease (Mpro) plays an essential role in viral replication, cleaving viral polyproteins into functional proteins. This makes Mpro an important drug target. Mpro consists of an N-terminal catalytic domain and a C-terminal α-helical domain (MproC). Previous studies have shown that peptides derived from a given protein sequence (self-peptides) can affect the folding and, in turn, the function of that protein. Since the SARS-CoV-1 MproC is known to stabilize its Mpro and regulate its function, we hypothesized that SARS-CoV-2 MproC-derived self-peptides may modulate the folding and the function of SARS-CoV-2 Mpro. To test this, we studied the folding of MproC in the presence of various self-peptides using coarse-grained structure-based models and molecular dynamics simulations. In these simulations of MproC and one self-peptide, we found that two self-peptides, the α1-helix and the loop between α4 and α5 (loop4), could replace the equivalent native sequences in the MproC structure. Replacement of either sequence in full-length Mpro should, in principle, be able to perturb Mpro function albeit through different mechanisms. Some general principles for the rational design of self-peptide inhibitors emerge: The simulations show that prefolded self-peptides are more likely to replace native sequences than those which do not possess structure. Additionally, the α1-helix self-peptide is kinetically stable and once inserted rarely exchanges with the native α1-helix, while the loop4 self-peptide is easily replaced by the native loop4, making it less useful for modulating function. In summary, a prefolded α1-derived peptide should be able to inhibit SARS-CoV-2 Mpro function.