Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 47 min ago
Peer-reviewedCC BY 3.0RSC Medicinal Chemistry

Downsizing macrocycles in melanocortin peptide analogues: thioether and lactam cyclization strategies to modulate hMC3/4R agonism and antagonism

  • Rosa Bellavita1
  • Luis E. Gimenez2
  • Savannah Y. Williams2
  • Ida Boccino1
  • Gennaro M. Bailo1
  • Roger D. Cone2,3,4
  • Paolo Grieco1
  • Francesco Merlino1
4 affiliations
  1. 1Department of Pharmacy, University of Naples Federico II Naples 80131 Italy
  2. 2Life Sciences Institute, University of Michigan Ann Arbor MI 48109 USA
  3. 3Department of Molecular and Integrative Physiology, University of Michigan Ann Arbor MI 48109 USA
  4. 4Department of Molecular, Cellular, and Developmental Biology, University of Michigan Ann Arbor MI 48109 USA
Read full textDOICite

Abstract

Stabilizing β-turn geometry through macrocyclization has been a key determinant of receptor selectivity and functional activity in melanocortin peptide ligands. In addition to conformational constraint, macrocycle size plays a critical role in modulating receptor recognition. In this study, we report a novel library of downsized MT-II and SHU-9119 analogues featuring 20- and 19-membered macrocycles, generated through lactam and thioether cyclization strategies while preserving the canonical His–dPhe/dNal(2)–Arg–Trp pharmacophore. Functional evaluation revealed that these reduced macrocycles retained activity at the human melanocortin-3 and -4 receptors (hMC3R and hMC4R), with key structural elements governing receptor preference and agonist versus antagonist behavior within this receptor subset. Three new hMC4R agonists were identified: the lactam-linked peptides 6 and 10 and the thioether-linked peptide 14. In addition, the thioether-linked peptide 15 exhibited weak partial agonist activity and functional antagonism at hMC4R. Notably, peptide 14 showed subnanomolar hMC4R agonist potency (pEC50 = 9.55) and 84-fold functional preference for hMC4R over hMC3R. These findings identify the 20-membered thioether-containing architecture as particularly favourable for achieving potent hMC4R agonism and enhanced functional preference over hMC3R.

Related

  1. Supramolecular Architecture of Chiral Macrocycles: Hierarchical Assembly and Confinement Effect for Enhanced Circularly Polarized Luminescence
    Xin Song, Xuefeng Zhu, Shengfu Wu +3
    Accounts of Materials ResearchPeer-reviewedLicence not statedFull text7 citedOrganic chemistryOpenAlex
  2. Electronic tuning of tetranuclear Cu(i)–pyrazolate macrocycles: anti-Kasha emission through high-lying triplet states of a C2F5-substituted complex
    Shinaj K. Rajagopal, Christian M. Peterson, Matthias Zeller +3
    Dalton transactions (Cambridge, England : 2003)Peer-reviewedCC BYFull textGeneral chemistryEurope PMC
  3. Elucidating the role of particle downsizing in offretite zeolites for dynamic CO2/N2 separation
    Risheng Wang, Sajjad Ghojavand, Edwin Clatworthy +4
    Chemical engineering journal. Green and sustainablePeer-reviewedCC BYGeneral chemistryHAL
  4. Substituent Effects on Anion Bonding and Disassembly of Hypervalent Iodine Macrocycles
    Samsul Arafin, Riya Krishnan, Maximilian S. Kersten +3
    ChemRxivPreprintCC BYFull textOrganic chemistryChemRxiv
  5. Salt-bridged macrocycles as building blocks for aqueous supramolecular nanotube formation
    Jacobo Veiga-Herrero, Isabel López-Martín, Eduardo Anaya-Plaza +2
    Chemical SciencePeer-reviewedCC BY-NC 3.0Full textOrganic chemistryPMC

Cite

BibTeXRIS
BibTeX
@article{bellavita2026downsizing,
  title = {{Downsizing macrocycles in melanocortin peptide analogues: thioether and lactam cyclization strategies to modulate hMC3/4R agonism and antagonism}},
  author = {Rosa Bellavita and Luis E. Gimenez and Savannah Y. Williams and Ida Boccino and Gennaro M. Bailo and Roger D. Cone and Paolo Grieco and Francesco Merlino},
  journal = {RSC Medicinal Chemistry},
  year = {2026},
  month = oct,
  doi = {10.1039/d6md00726k},
  url = {https://doi.org/10.1039/d6md00726k},
  note = {CC BY 3.0},
}
RIS
TY  - JOUR
TI  - Downsizing macrocycles in melanocortin peptide analogues: thioether and lactam cyclization strategies to modulate hMC3/4R agonism and antagonism
AU  - Rosa Bellavita
AU  - Luis E. Gimenez
AU  - Savannah Y. Williams
AU  - Ida Boccino
AU  - Gennaro M. Bailo
AU  - Roger D. Cone
AU  - Paolo Grieco
AU  - Francesco Merlino
PY  - 2026
DA  - 2026/10/21
JO  - RSC Medicinal Chemistry
DO  - 10.1039/d6md00726k
UR  - https://doi.org/10.1039/d6md00726k
AB  - Stabilizing β-turn geometry through macrocyclization has been a key determinant of receptor selectivity and functional activity in melanocortin peptide ligands. In addition to conformational constraint, macrocycle size plays a critical role in modulating receptor recognition. In this study, we report a novel library of downsized MT-II and SHU-9119 analogues featuring 20- and 19-membered macrocycles, generated through lactam and thioether cyclization strategies while preserving the canonical His–dPhe/dNal(2)–Arg–Trp pharmacophore. Functional evaluation revealed that these reduced macrocycles retained activity at the human melanocortin-3 and -4 receptors (hMC3R and hMC4R), with key structural elements governing receptor preference and agonist versus antagonist behavior within this receptor subset. Three new hMC4R agonists were identified: the lactam-linked peptides 6 and 10 and the thioether-linked peptide 14. In addition, the thioether-linked peptide 15 exhibited weak partial agonist activity and functional antagonism at hMC4R. Notably, peptide 14 showed subnanomolar hMC4R agonist potency (pEC50 = 9.55) and 84-fold functional preference for hMC4R over hMC3R. These findings identify the 20-membered thioether-containing architecture as particularly favourable for achieving potent hMC4R agonism and enhanced functional preference over hMC3R.
SN  - 2632-8682
ER  -