Targeting Cyclophilin A and CD147 to Inhibit Replication of SARS-CoV-2 and SARS-CoV-2-Induced Inflammation.

Abstract

Identification and development of effective therapeutics for COVID-19 are still urgently needed. The CD147/Spike interaction is involved in the SARS-CoV-2 invasion process, in addition to 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-CTD, and the IC50 is 0.23 µM and 0.17 µM respectively. Due to high homology, CsA also had inhibitory effects on SARS-CoV and MERS-CoV, and the IC50 is 3.2 µM and 2.8 µM respectively. Finally, we generated a formulation-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. Significance Statement New SARS-CoV-2 variants and other pathogenic CoVs are continually emerging and new broad-spectrum anti-CoV therapy is urgently needed. We found that binding sites of CyPA/CsA overlap with CyPA/N-CTD and CyPA/CD147 binding, and CsA shows the potential to inhibit the activity of invasion or replication driven by CyPA during SARS-CoV-2 infection. Here, we provide new evidence for targeting CyPA in the treatment of COVID-19, as well as the potential of development CyPA inhibitors for broad-spectrum inhibition of CoVs.