Article ; Online: Computational design of a cyclic peptide that inhibits the CTLA4 immune checkpoint.
RSC medicinal chemistry
2023 Volume 14, Issue 4, Page(s) 658–670
Abstract: Proteins involved in immune checkpoint pathways, such as CTLA4, PD1, and PD-L1, have become important targets for cancer immunotherapy; however, development of small molecule drugs targeting these pathways has proven difficult due to the nature of their ... ...
| Abstract | Proteins involved in immune checkpoint pathways, such as CTLA4, PD1, and PD-L1, have become important targets for cancer immunotherapy; however, development of small molecule drugs targeting these pathways has proven difficult due to the nature of their protein-protein interfaces. Here, using a hierarchy of computational techniques, we design a cyclic peptide that binds CTLA4 and follow this with experimental verification of binding and biological activity, using bio-layer interferometry, cell culture, and a mouse tumor model. Beginning from a template excised from the X-ray structure of the CTLA4:B7-2 complex, we generate several peptide sequences using flexible docking and modeling steps. These peptides are cyclized head-to-tail to improve structural and proteolytic stability and screened using molecular dynamics simulation and MM-GBSA calculation. The standard binding free energies for shortlisted peptides are then calculated in explicit-solvent simulation using a rigorous multistep technique. The most promising peptide, cyc(EIDTVLTPTGWVAKRYS), yields the standard free energy -6.6 ± 3.5 kcal mol |
|---|---|
| Language | English |
| Publishing date | 2023-03-01 |
| Publishing country | England |
| Document type | Journal Article |
| ISSN | 2632-8682 |
| ISSN (online) | 2632-8682 |
| DOI | 10.1039/d2md00409g |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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