2. Academic Validation
  3. On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents

On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents

  • J Med Chem. 2025 May 8;68(9):9623-9637. doi: 10.1021/acs.jmedchem.5c00396.
Robin Kryštůfek 1 2,  Václav Verner 1,  Pavel Šácha 1 3,  Martin Hadzima 1,  Filip Trajhan 1 4,  Jana Starková 1,  Eva Tloušt'ová 1,  Alexandra Dvořáková 1,  Adam Pecina 1,  Jiří Brynda 1 5,  Karel Chalupský 1,  Miroslav Hájek 1,  Michael J Boucher 6,  Pavel Majer 1,  Jan Řezáč 1,  Hiten D Madhani 6,  Charles S Craik 7,  Jan Konvalinka 1 3
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic.
  • 2 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic.
  • 3 Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic.
  • 4 Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, Prague 2 12843, Czech Republic.
  • 5 Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, Prague 4 14220, Czech Republic.
  • 6 Department of Biochemistry & Biophysics, University of California San Francisco, UCSF Genentech Hall, 600 16th St Rm N374, San Francisco, California 94158, United States.
  • 7 Department of Pharmaceutical Chemistry, University of California San Francisco, UCSF Genentech Hall, 600 16th St Rm S512, San Francisco, California 94158, United States.
PMID: 40262033 DOI: 10.1021/acs.jmedchem.5c00396
Abstract

Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening Fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and Antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent Antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in Antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

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