Toward development of generic inhibitors against the 3C proteases of picornaviruses

Abstract

Development of novel antivirals, which requires knowledge of the viral life cycle in molecular detail, is a daunting task, involving extensive investments, and frequently resulting in failure. As there exist significant commonalities among virus families in the manner of host interaction, identifying and targeting common rather than specific features may lead to the development of broadly useful antivirals. Here, we have targeted the 3C protease of Hepatitis A Virus (HAV), a feco‐orally transmitted virus of the family Picornaviridae, for identification of potential antivirals. The 3C protease is a viable drug target as it is required by HAV, as well as by other picornaviruses, for post‐translational proteolysis of viral polyproteins and for inhibiting host innate immune pathways. Computational screening, followed by chemical synthesis and experimental validation resulted in identification of a few compounds which, at low micromolar concentrations, could inhibit HAV 3C activity. These compounds were further tested experimentally against the 3C protease of Human Rhinovirus, another member of the Picornaviridae family, with comparable results. Computational studies on 3C proteases from other members of the picornavirus family have indicated that the compounds identified could potentially be generic inhibitors for picornavirus 3C proteases.

Evaluation of Potential Anti-Hepatitis A Virus 3C Protease Inhibitors Using Molecular Docking

“…We ran the screening and docking of potential small molecule inhibitors in the crystal structure of HAV 3C protease (PDB ID 2CXV) utilizing the same binding pocket that was previously reported ( Figure 1 A–D) [ 12 ].…”

“…HAV 3C also inhibits HAV IRES-dependent translation and the polypyrimidine tract-binding protein (PTB) to give way to subsequent HAV genome replication [ 8 ]. Thus, as HAV 3C protein plays an important role, it is one of the attractive targets of anti-HAV drugs [ 9 , 10 , 11 , 12 ].…”

Cell Culture Systems and Drug Targets for Hepatitis A Virus Infection

“…HAV 3C also induced caspase-independent cell death with the vacuolization of lysosomal and endosomal organelles [88]. There are several reports on the development of HAV 3C inhibitors [13,81].…”

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).…”

“…Over the past years, our appreciation of the natural 3C/3CL pro diversity and conservation of specific residues has been steadily improved by comparative genomics, while our understanding of the roles and properties of these proteases in viral replication was largely based on just a few viruses of the above taxa, with a strong focus on viruses that (may) infect humans. Specifically, the structural characterization of 3C/ 3CL pro s remained limited to those encoded by several mammalian viruses and one avian virus of the Picornaviridae, Coronaviridae, Arteriviridae, Caliciviridae, and Astroviridae, and plant Potyviridae and Sobemovirus (Matthews et al, 1994;Banerjee et al, 2018;Phan et al, 2002;Nunn et al, 2005;Speroni et al, 2009;Gayathri et al, 2006;Damalanka et al, 2018;Weerawarna et al, 2016;Galasiti Kankanamalage et al, 2017;Takahashi et al, 2013;Kim et al, 2012;Muhaxhiri et al, 2013;Allaire et al, 1994;Anand et al, 2002Anand et al, , 2003Bergmann et al, 1997;Xue et al, 2008;Yang et al, 2003;Barrette-Ng et al, 2002). All these proteases have substrate specificities that are critically determined by the P1 position.…”