Cytotoxic T-Lymphocyte Associated protein-4 (CTLA-4) is an immune checkpoint protein that plays an important role in self-tolerance and suppression of immune responses. Cancer cells often produce an abundance of CTLA-4 proteins. The association of CTLA-4 with proteins of the B7 family on T-lymphocytes, such as CD-80 and CD-86, can allow many types of cancer cells to evade destruction by the immune system. Hence, blocking the complex formation between CTLA-4 and B-7 family protein can trigger an immune response against cancer cells. We analyzed the X-ray crystal structure of the CTLA-4 complexed with CD-86, one of the B-7 family protein,s and designed <i>de novo</i> cyclic peptides that bind to CTLA-4 at the same site where the CD-86 protein binds. In molecular dynamics simulations, some of the designed cyclic peptides stayed bound with CTLA-4 for almost half of a microsecond. Additionally, we calculated the standard binding free energy for two of these peptides by a rigorous method, obtaining a dissociation constant in the nanomolar range. These computational results suggest that these designed cyclic peptides are potential candidates for immune checkpoint inhibitors.

Computational design of peptides for cancer immunotherapy.

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.