6TVJ

Solution structure of PD-i3 peptide inhibitor of the human PD-1 extracellular domain

Summary for 6TVJ

• Entry DOI: 10.2210/pdb6tvj/pdb
• Related: 6TT6
• NMR Information: BMRB: 34474
• Descriptor: PD-i3 peptide (1 entity in total)
• Functional Keywords: immunotherapy, heterochiral peptide, computational design, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 1345.52

Authors

Guardiola, S.,Varese, M.,Garcia, J.,Giralt, E. (deposition date: 2020-01-09, release date: 2021-01-27, Last modification date: 2024-10-16)

Primary citation

Guardiola, S.,Varese, M.,Roig, X.,Sanchez-Navarro, M.,Garcia, J.,Giralt, E.
Target-templated de novo design of macrocyclic d-/l-peptides: discovery of drug-like inhibitors of PD-1.
Chem Sci, 12:5164-5170, 2021

PubMed Abstract: Peptides are a rapidly growing class of therapeutics with various advantages over traditional small molecules, especially for targeting difficult protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing bioactive cyclic topologies that go beyond natural l-amino acids. Here, we report a generalizable framework that exploits the computational power of Rosetta, in terms of large-scale backbone sampling, side-chain composition and energy scoring, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we developed two new inhibitors ( and ) of programmed cell death 1 (PD-1), a key immune checkpoint in oncology. A comprehensive biophysical evaluation was performed to assess their binding to PD-1 as well as their blocking effect on the endogenous PD-1/PD-L1 interaction. Finally, NMR elucidation of their in-solution structures confirmed our design approach.

PubMed: 34163753
DOI: 10.1039/d1sc01031j

Experimental method

SOLUTION NMR