PROTAC targeting cyclophilin A controls virus-induced cytokine storm

Heqiao Li; Wenxian Yang; Huizi Li; Xiaoyuan Bai; He Zhang; Wenhui Fan; Wenjun Liu; Lei Sun

doi:10.1016/j.isci.2023.107535

PROTAC targeting cyclophilin A controls virus-induced cytokine storm

iScience. 2023 Aug 3;26(9):107535. doi: 10.1016/j.isci.2023.107535. eCollection 2023 Sep 15.

Authors

Heqiao Li^{1

2

3}, Wenxian Yang^{1

2}, Huizi Li^{2

3}, Xiaoyuan Bai^{1

2}, He Zhang¹, Wenhui Fan², Wenjun Liu^{1

2

3}, Lei Sun^{2

3}

Affiliations

¹ Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
³ Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.

Abstract

Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms.

Keywords: Immunology; Molecular biology; Virology.