Sirolimus plus Dactinomycin
Sirolimus, an inhibitor of mTOR with both antifungal and antineoplastic properties, has demonstrated to improve outcomes in patients with severe H1N1 pneumonia and acute respiratory failure50. The mTOR signaling plays an essential role for MERS-CoV infection66. Dactinomycin, also known actinomycin D, is an approved RNA synthesis inhibitor for treatment of various cancer types. An early study showed that dactinomycin (1 μg/ml) inhibited the growth of feline enteric CoV67. As shown in Fig. 6b, our network analysis shows that sirolimus and dactinomycin synergistically target HCoV-associated host protein subnetwork by “Complementary Exposure” pattern, offering potential combination regimens for treatment of HCoV. Specifically, sirolimus and dactinomycin may inhibit both mTOR signaling and RNA synthesis pathway (including DNA topoisomerase 2-alpha (TOP2A) and DNA topoisomerase 2-beta (TOP2B)) in HCoV-infected cells (Fig. 6b).