2. Academic Validation
  3. A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury

A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury

  • J Med Chem. 2020 Nov 12;63(21):12853-12872. doi: 10.1021/acs.jmedchem.0c01236.
Patrick G Dougherty 1 2,  Manjula Karpurapu 3,  Amritendu Koley 1,  Jessica K Lukowski 4,  Ziqing Qian 1 2,  Teja Srinivas Nirujogi 3 5,  Luiza Rusu 3,  Sangwoon Chung 3,  Amanda B Hummon 1 6,  Hao W Li 7,  John W Christman 3,  Dehua Pei 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Ave., Columbus, Ohio 43210, United States.
  • 2 Entrada Therapeutics, 50 Northern Avenue, Boston, Massachusetts 02210, United States.
  • 3 Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, Ohio 43210, United States.
  • 4 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
  • 5 East Liverpool City Hospital, 425 W 5th Street, East Liverpool, Ohio 43920, United States.
  • 6 Comprehensive Cancer Center, The Ohio State University, Columbus Ohio, 43210, United States.
  • 7 Columbia Center for Translational Immunology, Columbia University, 650 W. 168th Street, New York, New York 10032, United States.
PMID: 33073986 DOI: 10.1021/acs.jmedchem.0c01236
Abstract

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase Calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between Calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited Calcineurin signaling in vitro and in vivo and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and Other inflammatory diseases.

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