2. Academic Validation
  3. Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in Plasmodium falciparum

Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in Plasmodium falciparum

  • ACS Infect Dis. 2023 Sep 15. doi: 10.1021/acsinfecdis.3c00310.
John M Bennett 1,  Kurt E Ward 2 3,  Ryan K Muir 4,  Stephanie Kabeche 5,  Euna Yoo 4 6,  Tomas Yeo 2 3,  Grace Lam 7,  Hao Zhang 8,  Jehad Almaliti 9,  Gabriel Berger 4,  Franco F Faucher 1,  Gang Lin 8,  William H Gerwick 10 9,  Ellen Yeh 4 11,  David A Fidock 2 3 12,  Matthew Bogyo 4 10
Affiliations

Affiliations

  • 1 Department of Chemistry, Stanford University, Stanford, California 94305, United States.
  • 2 Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, United States.
  • 3 Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Medical Center, New York, New York 10032, United States.
  • 4 Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 5 Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 6 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 7 Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California 94304, United States.
  • 8 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York 10065, United States.
  • 9 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States.
  • 10 Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92037, United States.
  • 11 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94304, United States.
  • 12 Division of Infectious Diseases, Columbia University Medical Center, New York, New York 10032, United States.
PMID: 37712594 DOI: 10.1021/acsinfecdis.3c00310
Abstract

The Plasmodium Proteasome is a promising antimalarial drug target due to its essential role in all Parasite lifecycle stages. Furthermore, Proteasome inhibitors have synergistic effects when combined with current first-line artemisinin and related analogues. Linear Peptides that covalently inhibit the Proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible, macrocyclic inhibitors of the Plasmodium falciparum Proteasome. We identified compounds with excellent potency and low cytotoxicity; however, the first generation suffered from poor microsomal stability. Further optimization of an existing macrocyclic scaffold resulted in an irreversible covalent inhibitor carrying a vinyl sulfone electrophile that retained high potency and low cytotoxicity and had acceptable metabolic stability. Importantly, unlike the parent reversible inhibitor that selected for multiple mutations in the Proteasome, with one resulting in a 5,000-fold loss of potency, the irreversible analogue only showed a 5-fold loss in potency for any single point mutation. Furthermore, an epoxyketone analogue of the same scaffold retained potency against a panel of known Proteasome mutants. These results confirm that macrocycles are optimal scaffolds to target the malarial Proteasome and that the use of a covalent electrophile can greatly reduce the ability of the Parasite to generate drug resistance mutations.

Keywords

Plasmodium falciparum;; antimicrobial resistance; cyclic peptides.

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