Targeting Cyclophilin A and CD147 to Inhibit Replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and SARS-CoV-2-Induced Inflammation.

Mol Pharmacol

Department of Pharmacology, School of Pharmacy (F.Y., C.L.), Minhang Hospital and School of Pharmacy, State Key Laboratory of Molecular Engineering of Polymers, Key Laboratory of Smart Drug Delivery Ministry of Education (A.W., W.L.), and Department of Pharmacology, School of Basic Medical Sciences (D.Z.), Fudan University, Shanghai, China; Max-von-Pettenkofer Institute, Ludwig-Maximilians-University of Munich and German Center for Infection Research, Munich, Germany (P.L., Y.M.-L., A.V.B.); Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, China (H.Z.); and S & T Global, Inc., Woburn, Massachusetts (Z.S.)

Published: December 2023

Identification and development of effective therapeutics for coronavirus disease 2019 (COVID-19) are still urgently needed. The CD147-spike interaction is involved in the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 invasion process in addition to angiotensin-converting enzyme 2 (ACE2). Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as cyclosporine A (CsA) and STG-175 can suppress the intracellular replication of SARS-CoV-2 by inhibiting the binding of CyPA to the SARS-CoV-2 nucleocapsid C-terminal domain (N-CTD), and the IC is 0.23 M and 0.17 M, respectively. Due to high homology, CsA also had inhibitory effects on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), and the IC is 3.2 M and 2.8 M, respectively. Finally, we generated a formulation of phosphatidylserine (PS)-liposome-CsA for pulmonary drug delivery. These findings provide a scientific basis for identifying CyPA as a potential drug target for the treatment of COVID-19 as well as for the development of broad-spectrum inhibitors for coronavirus via targeting CyPA. Highlights: 1) SARS-CoV-2 infects cells via the binding of its S protein and CD147; 2) binding of SARS-CoV-2 N protein and CyPA is essential for viral replication; 3) CD147 and CyPA are potential therapeutic targets for SARS-CoV-2; and 4) CsA is a potential therapeutic strategy by interrupting CD147/CyPA interactions. SIGNIFICANCE STATEMENT: New severe acute respiratory syndrome coronavirus (SARS-CoV)-2 variants and other pathogenic coronaviruses (CoVs) are continually emerging, and new broad-spectrum anti-CoV therapy is urgently needed. We found that binding sites of cyclophilin A/cyclosporin A (CyPA/CsA) overlap with CyPA/N-CTD (nucleocapsid C-terminal domain), which shows the potential to target CyPA during SARS-CoV-2 infection. Here, we provide new evidence for targeting CyPA in the treatment of coronavirus disease 2019 (COVID-19) as well as the potential of developing CyPA inhibitors for broad-spectrum inhibition of CoVs.

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Source
http://dx.doi.org/10.1124/molpharm.122.000587DOI Listing

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