9NWZ

LR4-814 peptide NMR structure

Summary for 9NWZ

• Entry DOI: 10.2210/pdb9nwz/pdb
• NMR Information: BMRB: 31236
• Descriptor: LR4-814 peptide (1 entity in total)
• Functional Keywords: lasso, designed, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 2216.43

Authors

Fry, D.C.,Burk, M.J. (deposition date: 2025-03-24, release date: 2025-04-02, Last modification date: 2025-09-17)

Primary citation

Lechner, A.,Jordan, P.A.,Machado da Cruz, G.C.,Lamson, J.,Gordon, J.,Okada, B.K.,Anderson, K.,Chaudhari, R.,Rosario, C.J.,Mikesell, J.,McPhee, S.A.,Burk, M.J.
Overcoming Immune Checkpoint Inhibitor Resistance with Potent, Selective Dual alpha v beta 6/8 Inhibitors Based on Engineered Lasso Peptides.
J.Am.Chem.Soc., 147:32522-32536, 2025

PubMed Abstract: Integrins αvβ6 and αvβ8 in the tumor microenvironment (TME) have been shown to activate immunosuppressive TGF-β, which serves as an important mechanism for immune checkpoint inhibitor resistance in a range of tumors. In this study, we demonstrate the utility of lasso peptides as versatile scaffolds for the design of new therapeutics. A series of highly potent and selective dual αvβ6/8 inhibitors were engineered through a combination of epitope scanning, computational design, and directed evolution, whereby inhibition was fine-tuned for two out of the eight related RGD-integrin receptors. NMR structures of two lasso peptide dual integrin inhibitors are provided. Facile conjugation chemistry with a small-molecule albumin binder afforded half-life extended lasso peptide analogs, including , which was fully characterized and shown to robustly and durably halt growth and regress anti-mPD-1-resistant ovarian and triple negative breast cancer tumors in mice when dosed in combination with the checkpoint inhibitor. These studies show that dual inhibition of αvβ6/8 integrins expressed in the TME represents an auspicious tumor-specific strategy to overcome TGF-β-driven resistance and enhance the antitumor efficacy of immune checkpoint inhibitors. Our ability to produce lasso peptides with high titers in fermenters has enabled the first detailed demonstration of their drug-like properties, including tunable in vivo pharmacokinetics and efficacy, thus paving the way for future advances using this promising modality derived from nature.

PubMed: 40891737
DOI: 10.1021/jacs.5c06142

Experimental method

SOLUTION NMR