Antivirals blocking entry of enteroviruses and therapeutic potential

Abstract

Viruses from the genus Enterovirus (EV) of the Picornaviridae family are known to cause diseases such as hand foot and mouth disease (HFMD), respiratory diseases, encephalitis and myocarditis. The capsid of EV is an attractive target for the development of direct-acting small molecules that can interfere with viral entry. Some of the capsid binders have been evaluated in clinical trials but the majority have failed due to insufficient efficacy or unacceptable off-target effects. Furthermore, most of the capsid binders exhibited a low barrier to resistance. Alternatively, host-targeting inhibitors such as peptides derived from the capsid of EV that can recognize cellular receptors have been identified. However, the majority of these peptides displayed low anti-EV potency (µM range) as compared to the potency of small molecule compounds (nM range). Nonetheless, the development of anti-EV peptides is warranted as they may complement the small-molecules in a drug combination strategy to treat EVs. Lastly, structure-based approach to design antiviral peptides should be utilized to unearth potent anti-EV peptides.

Keywords: Antiviral compound; Antiviral peptide; Enterovirus; Picornaviridae.

Fig. 1

Enterovirus capsid organization and features. a Overall view of the enterovirus capsid comprising the VP1 (red), VP2 (blue) and VP3 (yellow). PDB ID: 4RQP [8]. The green lines indicate the boundaries of one pentamer. The black lines indicate the icosahedral symmetric subunit. The five, three, twofold symmetry axes are labeled and highlighted in grey. The cyan lines separate VP1 (red), VP2 (blue) and VP3 (yellow). Black arrows indicate the canyon region and the fivefold axis region formed by five VP1. b Canonical enterovirus protomer formed by VP1 (red), VP2 (blue), VP3 (yellow) and VP4 (green). PDB ID: 6GZV [9]. The canyon is highlighted in grey transparent and is indicated by a black arrow. Antiviral compounds that bind to the two binding pockets which are VP1 hydrophobic pocket and VP1–VP3 interprotomer pocket are shown in cyan and magenta, respectively

Fig. 2

The structure of poliovirus in complex with PVR (PDB ID: 3EPD) [94]. a Overall view of the canonical picornavirus protomer with the capsid proteins VP1, VP2, VP3 and VP4 are shown in red, yellow, blue and green, respectively. The apical domain of PVR that binds to the canyon of the protomer is shown magenta. b The amino acids that make contacts with the canyon are shown in sticks and labeled

Fig. 3

Three-dimensional structure of EV-A71 in complex with SCARB2 (PDB: 6I2K) [18]. The EV-A71 capsid proteins VP1, VP2, VP3 and VP4 are shown in red, yellow, blue and green, respectively. The receptor SCARB2 is shown in cyan. VP2 EF loop and VP1 GH loop of EV-A71 interact with α5 and α7 helices of SCARB2 to form the interface of the complex