Antiviral therapeutic approaches for human rhinovirus infections

Casanova, Victor; Sousa, Filipa H; Stevens, Craig; Barlow, Peter G

A number of studies have focused upon the effectiveness of the compound pleconaril against human RV. Pleconaril (3-(3,5-dimethyl-4-((3-(3-methyl-5-isoxazolyl)propyl)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole) is known to display broad spectrum antiviral activity against a range of viral pathogens. It is known to bind to hydrophobic pockets within viral capsids, altering binding of the viral pathogen to host cell receptors and blocking uncoating [36] . In RV and others, this is believed to take place in the VP1 protein, the largest and most exposed surface protein of the capsid [37] . One comprehensive study examined the effectiveness of pleconaril against a selection of five RV serotypes (RV-2, RV-14, RV-16, RV-39 and RV-Hanks [later serotyped as A21]) and 46 clinical isolates using in vitro cytopathic effect (CPE) inhibition assays [38] . The study demonstrated that the compound had effective antiviral activity against the five serotypes (median EC50 of 0.02 μg/ml) and against the majority of the untyped clinical isolates. Two separate studies also demonstrated findings in accord with this, showing antiviral activity of pleconaril against RV-14 and RV-87 [33, 34] . Interestingly, analysis of several RV serotypes has also assessed structural features of amino acids that make up the VP1 protein, and has identified several common sequences and mutations that confer natural resistance to capsid binding compounds such as pleconaril, as well as those that could arise as a result of antiviral drug treatment [39, 40] . A number of human experimental pleconaril administration studies have found that pleconaril could offer a tangible treatment option for RV infection as volunteers treated with this drug appeared to show less clinical symptomology and lower recovery of picornaviruses than controls [41, 42] . However, varying virus serotype susceptibility to pleconaril did appear to play a significant role in the efficacy of the treatment and clinical outcome [43] . However, studies into pleconaril analogs with enhanced activity against RV are still ongoing [44] .