4.8. Sirolimus (Rapamune)
Sirolimus is a natural macrolide (Figure S5) obtained from Streptomyces hygroscopicus. It was first approved by the U.S. FDA in 1999 and is orally used for lymphangioleiomyomatosis and renal transplantation. Mechanistically, the drug is an immunosuppressive agent and an inhibitor of the mammalian target of rapamycin (mTOR). Sirolimus forms an immunosuppressive complex with FK-binding protein-12, and subsequently, the complex inhibits the regulatory kinase, mTOR. This inhibition suppresses cytokine mediated proliferation of T and B cells as well as the antibody production [180,181]. Furthermore, the drug may influence the virus because mTOR complex 1 is involved in the replication of various viruses, including coronavirus [182,183,184]. Furthermore, in vitro studies demonstrated a specific inhibitory activity against MERS-CoV infection by sirolimus [184]. In an open-label, prospective randomized study in H1N1 pneumonia patients, treatment with sirolimus and corticosteroids combination for two weeks alleviated hypoxia, shortened the mechanical ventilation duration, and improved multi-organ function [185]. Accordingly, sirolimus is being tested for the treatment of COVID-19 patients either alone or in combination with hydroxychloroquine in several clinical trials. Likewise, RTB101 (dactolisib), another mTOR inhibitor and phosphoinositide 3-kinase inhibitor, is also being tested in COVID-19 patients (NCT04409327; n = 550).