Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability

Md Shafikur Rahman, Shikha Kumari, Shiva Hadi Esfahani, Saeideh Nozohouri, Srinidhi Jayaraman, Nihar Kinarivala, Joanna Kocot, Andrew Baez, Delaney Farris, Thomas J. Abbruscato, Vardan T. Karamyan, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety and possess single-digit micromolar potency over 40-fold greater than the hit scaffolds. These compounds exhibit 5-fold increased brain penetration, significant selectivity over highly homologous peptidases, greater than 65-fold increase in mouse brain stability, and 'drug-like' fraction unbound in the brain.

Original languageEnglish (US)
Pages (from-to)12705-12722
Number of pages18
JournalJournal of Medicinal Chemistry
Volume64
Issue number17
DOIs
StatePublished - Sep 9 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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