ORCID Profile
0000-0002-7583-4961
Current Organisations
The Francis Crick Institute
,
Imperial College London
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Publisher: Wiley
Date: 02-05-2019
Abstract: Loops at protein-protein interfaces are a rich source of peptide leads that have high specificity and low toxicity. Although such peptides typically need to be constrained to overcome thermodynamic and metabolic limitations, design guidelines to obtain a successfully constrained peptides, and thus facilitate the transition from loop to drug, are relatively poorly formulated. In this work, we surveyed the structures of interface loops and found the position of the terminal residues to be a key determinant of conformation. We used this knowledge to improve the process of molecular grafting, a valuable approach for constraining and stabilising peptides by fusing them to a suitable scaffold. We show that an informed choice of where a loop is "anchored" to a scaffold improves its form and function. This knowledge can help guide the choice of loop and its matching scaffold, and thus increase the success rate for designing stable and potent peptide drug leads.
Publisher: Wiley
Date: 02-05-2019
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Chemical Society (ACS)
Date: 21-06-2021
Publisher: American Chemical Society (ACS)
Date: 18-10-2021
DOI: 10.1021/JACS.1C08132
Abstract: Peptides have potential to be developed into immune checkpoint inhibitors, but the target interfaces are difficult to inhibit. Here, we explored an approach to mimic the binding surface of PD-1 to design inhibitors. Mimicking native PD-1 resulted in a mimetic with no activity. However, mimicking an affinity-optimized PD-1 resulted in the peptide mimetic MOPD-1 that displayed nanomolar affinity to PD-L1 and could inhibit PD-1:PD-L1 interactions in both protein- and cell-based assays. Mutagenesis and structural characterization using NMR spectroscopy and X-ray crystallography revealed that binding residues from the high affinity PD-1 are crucial for the bioactivity of MOPD-1. Furthermore, MOPD-1 was extremely stable in human serum and inhibited tumor growth
Publisher: American Chemical Society (ACS)
Date: 21-04-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Huawu Yin.