Individual and common inhibitors of coronavirus and picornavirus main proteases

Abstract

a b s t r a c tPicornaviruses (PV) and coronaviruses (CoV) are positive-stranded RNA viruses which infect millions of people worldwide each year, resulting in a wide range of clinical outcomes. As reported in this study, using high throughput screening against 6800 small molecules, we have identified several novel inhibitors of SARS-CoV 3CL pro with IC 50 of low lM. Interestingly, one of them equally inhibited both 3C pro and 3CL pro from PV and CoV, respectively. Using computer modeling, the structural features of these compounds as individual and common protease inhibitors were elucidated to enhance our knowledge for developing anti-viral agents against PV and CoV.

Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors

“…Compounds with a pyrazole ring surrounded by three hydrophobic groups were also reported to inhibit 3C proteases of human picornaviruses, such as rhinoviruse, enteroviruse, and coxsackieviruse, in addition to 3CL pro of coronaviruses. [29] Efforts are being made to co-crystallize these compounds with the enzymes. Cell-based assay would be needed to facilitate further development into more potent inhibitors which could have clinically usefulness.…”

Antiviral activity of zinc salts against transmissible gastroenteritis virus in vitro

“…This reduction of viral proteins could be a result of the inhibition of previous stages of viral replication, but again there is also evidence that Zn could directly inhibit the proteolytic cleavage of viral polypeptides (Korant and Butterworth, 1976). Potential points of action against TGEV might be a chymotrypsin-like protease that is responsible for the cleavage of polyproteins into functional proteins, and which is highly conserved in coronaviruses (Kuo et al, 2009), or a papain-like protease which, in case of the SARS-CoV, was shown to be potently inhibited by Zn ions (Han et al, 2005).…”

Structural basis for catalysis and substrate specificity of a 3C-like cysteine protease from a mosquito mesonivirus

“…These substrate https://doi.org/10.1016/j.virol.2019.05.001 Received 10 April 2019; Received in revised form 30 April 2019; Accepted 1 May 2019 residues are accommodated in a protease substrate pocket that generally includes a highly conserved His residue (which differs from the catalytic His) and another residue, often Ser or Thr, which together define the S1 subsite homologous to that of cellular chymotrypsin-like proteases (Bazan and Fletterick, 1988;Gorbalenya et al, 1989a). These residues are generally considered valuable targets for the development of broadly acting antiviral drugs (Kuo et al, 2009;Yang et al, 2005;Banerjee et al, 2018;Pillaiyar et al, 2016).…”