SPECTRUM AND CHARACTERISTICS OF THE VIRUS INHIBITORY ACTION OF 2-(Α-Hydroxybenzyl)-Benzimidazole

Abstract

Recently, selective inhibition of poliovirus b y 2-(a-hydroxybenzyl)-benzimidazole was described (1-3).Following the original report (1) concerning inhibition of poliovirus by 2-(o~-hydroxybenzyl)-benzimidazole (HBB), it was shown in quantitative studies (2, 3) that HBB inhibits the multiplication and the cytopathic effects of poliovirus type 2 in monkey kidney cells, but does not inhibit influenza B virus in the same cell system or in the chorioallantoic membrane from embryouated chicken eggs. At concentrations sufficient to cause marked inhibition of poliovirus, the compound had no effect, or only a slight effect, on the morphologic appearance of monkey kidney cells. Thus, HBB showed significant biological selectivity in its virus in- hibitory action. Inhibition of viral cytopathic effects appeared to be due to inhibition of virus multiplication. It should be emphasized that HBB was virostatic, but not virocidal, for poliovirus.Studies of structure-activity relationships with HBB and related compounds suggested (3) that the hydroxybenzyl grouping at position 2 in the imidazole ring was of fundamental importance for the selective virus inhibitory action of HBB (of. Text- fig. 1). HBB could not readily be considered a close structural analog of any known metabolite. Furthermore, the fact that the compound did not damage cells at virus inhibitory concentrations, made it seem nnlilrely that HBB was acting as an antagonist of a metabolite required by both the host cell and the virus.These findings suggested a new approach to the study of mechanism of virus multiplication: it appeared that with the aid of HBB and related corn-* Aided by a grant from The National Foundation.

The picornavirus replication inhibitors HBB and guanidine in the echovirus-9 system: the significance of viral protein 2C

“…GMK monolayers were infected with the respective virus and the virus-induced cell damage (CPE) was estimated by microscopic examination (Eggers & Tamm, 1961). The average of at least two independent values, differing by not more than 50 %, was taken.…”

Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds

“…Replication inhibitors could be classified into directacting antivirals and host-targeting antivirals. Viral proteins 2A, 2C, 3C, and 3D have been identified as the targets of direct-acting antivirals, including elastase inhibitors (9), guanidine hydrochloride (GuHCl) and related compounds (10)(11)(12)(13), rupintrivir (AG7088) (14,15), and gliotoxin (16), respectively. As host proteins, eIF4A, GBF1, and phosphatidylinositol 4-kinase III beta (PI4KB) have been identified as the targets of the host-targeting antivirals hippuristanol, brefeldin A, PIK93, and enviroxime (17)(18)(19)(20)(21)(22)(23).…”

Phosphatidylinositol 4-Kinase III Beta Is a Target of Enviroxime-Like Compounds for Antipoliovirus Activity

“…GuHCl inhibits the initiation of negative-strand RNA synthesis by targeting viral proteins 2C and/or 2BC (8,11,16). GuHCl and some benzimidazole derivatives, including 2-(alpha-hydroxybenzyl)-benzimidazole (26), MRL-1237 (45), and TBZE-029 (22), belong to a group of 2C inhibitors in terms of the resistance mutations in the 2C-encoding region. Enviroxime inhibits positive-strand RNA synthesis by preventing normal formation of the replication complex, possibly by targeting viral proteins 3A and/or 3AB, although its direct interaction with the 3A protein was not detected (15,29,50).…”