Anti-herpes simplex virus efficacies of 2-aminobenzamide derivatives as novel HSP90 inhibitors.
After the widespread use of the acyclic purine nucleoside analogues for therapy of herpes simplex virus (HSV) infection since the 1980s, new antiviral strategies are urgently needed to counter the emergence of drug-resistant clinical isolates. In this report, we define the anti-HSV efficacies of three optimized 2-aminobenzamide derivatives in vitro and in vivo. The synthetic analogues SNX-25a, SNX-2112 and SNX-7081, which selectively bind to the N-terminal ATP pocket of heat shock protein 90 (HSP90), exhibited significant anti-HSV-1 and HSV-2 activities at non-cytotoxic concentrations in Vero cells, with EC(50) values close to that of acyclovir (ACV). The in vivo antiviral potentials were then confirmed using a herpes simplex keratitis (HSK) rabbit model, where eye gels containing 0.1% or 0.025% SNX-25a displayed the highest efficacies against HSV-1 infection, which were better than that obtained with 0.1% ACV. SNX-2112 and SNX-7081 gels were also effective against HSV-1 with different magnitude of activities. Our results for the first time confirmed the anti-HSV efficacies of these 2-aminobenzamide derivatives and suggest that with alternative mechanisms of action these novel HSP90 inhibitors, especially SNX-25a, could be potent as new anti-HSV clinical trial candidates.
Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, PR China.
Yang-Fei
YF
Xiang
Chui-Wen
CW
Qian
Guo-Wen
GW
Xing
Jing
J
Hao
Min
M
Xia
Yi-Fei
YF
Wang
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology
D000998:Antiviral Agents; D018841:HSP90 Heat-Shock Proteins; D062367:ortho-Aminobenzoates; C000219:anthranilamide