Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor

Edin Muratspahić; Kristine Deibler; Jianming Han; Nataša Tomašević; Kirtikumar B. Jadhav; Aina-Leonor Olivé-Marti; Nadine Hochrainer; Roland Hellinger; Johannes Koehbach; Jonathan F. Fay; Mohammad Homaidur Rahman; Lamees Hegazy; Timothy W. Craven; Balazs R. Varga; Gaurav Bhardwaj; Kevin Appourchaux; Susruta Majumdar; Markus Muttenthaler; Parisa Hosseinzadeh; David J. Craik; Mariana Spetea; Tao Che; David Baker; Christian W. Gruber

doi:10.1038/s41467-023-43718-w

Titel

Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor

Autor*in

Edin Muratspahić

Institute for Protein Design, University of Washington

Kristine Deibler

Novo Nordisk Research Center Seattle

Jianming Han

Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine

... show all

Abstract

Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA–KOR–Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.

Stichwort

PeptidesProtein designReceptor pharmacology

Objekt-Typ

journal article

Sprache

Englisch [eng]

Persistent identifier

phaidra.univie.ac.at/o:2081612

DOI

10.1038/s41467-023-43718-w

Erschienen in

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