Research ArticleInfectious diseases

A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections

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Science Translational Medicine  16 Jun 2021:
Vol. 13, Issue 598, eabf8668
DOI: 10.1126/scitranslmed.abf8668

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Inhibiting herpes simplex virus

Although current treatments for herpes simplex viruses (HSV) have improved considerably over the past few decades, they remain unable to treat latent infection. Here, Gege et al. developed and tested IM-250, a helicase-primase inhibitor, as a means of treating both active and latent HSV infection. IM-250 showed favorable pharmacokinetics and safety and demonstrated in vitro anti-HSV activity. To evaluate the efficacy of IM-250 treatment in vivo, the authors established challenge models of both HSV-1 in mice and HSV-2 in guinea pigs. Treatment of mice lethally infected with a strain of HSV-1 increased survival, and treatment of guinea pigs latently infected with HSV-2 prevented recurrent disease. Thus, IM-250 is an attractive candidate helicase-primase inhibitor that merits further development as an HSV therapeutic.

Abstract

More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting the viral polymerase is somewhat effective but limited by poor exposure in the nervous system, and latent infections are not affected by therapy. Here, we report on an inhibitor of HSV helicase-primase with potent in vitro anti-herpes activity, a different mechanism of action, a low frequency of HSV resistance, and a favorable pharmacokinetic and safety profile. Improved target tissue exposure results in superior efficacy in preventing and treating HSV infection and disease in animal models as compared to standard of care. Therapy of primary HSV infections with drug candidate IM-250 {(S)-2-(2′,5′-difluoro-[1,1′-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfon-imidoyl)thiazol-2-yl)acetamide} not only reduces the duration of disease symptoms or time to healing but also prevents recurrent disease in guinea pigs. Treatment of recurrent infections reduces the frequency of recurrences and viral shedding, and, unlike nucleosidic drugs, IM-250 remains effective for a time after cessation of treatment. Hence, IM-250 has advantages over standard-of-care therapies and represents a promising therapeutic for chronic HSV infection, including nucleoside-resistant HSV.

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