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

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.

Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer’s Disease (AD); Underwhelming Evidence against

“…Nonetheless, all the evidence provides increasing support for further clinical trials which, in this author's opinion, should treat patients (at least HSV1-seropositive APOE-ε4 carriers) not only with VCV, but also with fucoidan, in view of its very different mode of action from that of blockers of HSV1 DNA replication. An alternative to VCV would be usage of a helicase primase inhibitor: interestingly, a study of a new such inhibitor, IM-250, which provides in animals sufficient brain exposure and a potentially superior dose regimen of once daily or even once weekly (rather than the usual twice daily) is in press [80]. Equally, or even more exciting would be a trial to investigate the apparent protective effects of vaccination, particularly of BCG, against the development of dementia, and a trial treating symptomatic sufferers of HSV1 with antiviral agents in their middle years, well before any signs of dementia are detectable.…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…In comparison to pritelivir, the resulting compound, IM-250 (29, Figure 10), revealed similar in vitro potency [IC50 HSV-1: 20 nM (pritelivir) vs 19 nM (IM-250)] but significantly reduced TPSA [106 Å 2 (pritelivir) vs 74 Å 2 (IM-250)] and increased lipophilicity [clogD pH 7.4: 2.0 (pritelivir) vs 3.3 (IM-250)]. [39] In preclinical evaluation, IM-250 displayed a long half-life, high exposure, good bioavailability and high CNS exposure in various species, which translated into superior in vivo activity in animal models compared to pritelivir. Innovative Molecules has subsequently announced the closing of a series A financing round in which 20 million euro was raised for the clinical evaluation of IM-250.…”

“…[38] Helicase-primase inhibitors offer a novel mode of action, but the clinical development of frontrunner compound pritelivir (28, Figure 10) has been hampered by CA off-target activity, aromatic, primary sulfonamide class-related side effects and limited CNS exposure. [39] Using pritelivir as a starting point, Kleymann and co-workers at Innovative Molecules reduced the topological polar surface area (TPSA) in order to improve the CNS exposure, for instance by replacing the pyridyl group by a difluorophenyl moiety. This modification also resulted in a significantly increased lipophilicity.…”

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

“…In contrast to currently used drugs, an effect on latent infection and virus reactivation is observed, which persists after withdrawal. Such results give hope that HSV infection will become curable in the future [ 130 ].…”