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 () and Christian W. Gruber ()
Additional contact information
Edin Muratspahić: Medical University of Vienna
Kristine Deibler: University of Washington
Jianming Han: University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine
Nataša Tomašević: Medical University of Vienna
Kirtikumar B. Jadhav: University of Vienna
Aina-Leonor Olivé-Marti: University of Innsbruck
Nadine Hochrainer: University of Innsbruck
Roland Hellinger: Medical University of Vienna
Johannes Koehbach: The University of Queensland
Jonathan F. Fay: University of Maryland Baltimore
Mohammad Homaidur Rahman: University of Health Sciences & Pharmacy in St. Louis
Lamees Hegazy: University of Health Sciences & Pharmacy in St. Louis
Timothy W. Craven: University of Washington
Balazs R. Varga: University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine
Gaurav Bhardwaj: University of Washington
Kevin Appourchaux: University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine
Susruta Majumdar: University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine
Markus Muttenthaler: University of Vienna
Parisa Hosseinzadeh: University of Oregon
David J. Craik: The University of Queensland
Mariana Spetea: University of Innsbruck
Tao Che: University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine
David Baker: University of Washington
Christian W. Gruber: Medical University of Vienna

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43718-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43718-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43718-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().