As shown in Fig. 5a, targets of both mercaptopurine and melatonin showed strong network proximity with HCoV-associated host proteins in the human interactome network. Recent in vitro and in vivo studies identified mercaptopurine as a selective inhibitor of both SARS-CoV and MERS-CoV by targeting papain-like protease53,54. Melatonin was reported in potential antiviral infection via its anti-inflammatory and antioxidant effects58–62. Melatonin indirectly regulates ACE2 expression, a key entry receptor involved in viral infection of HCoVs, including 2019-nCoV/SARS-CoV-2 (ref. 33). Specifically, melatonin was reported to inhibit calmodulin and calmodulin interacts with ACE2 by inhibiting shedding of its ectodomain, a key infectious process of SARS-CoV72,73. JUN, also known as c-Jun, is a key host protein involving in HCoV infectious bronchitis virus74. As shown in Fig. 6d, mercaptopurine and melatonin may synergistically block c-Jun signaling by targeting multiple cellular targets. In summary, combination of mercaptopurine and melatonin may offer a potential combination therapy for 2019-nCoV/SARS-CoV-2 by synergistically targeting papain-like protease, ACE2, c-Jun signaling, and anti-inflammatory pathways (Fig. 6d). However, further experimental observations on ACE2 pathways by melatonin in 2019-nCoV/SARS-CoV-2 are highly warranted.