Small molecule fights active and latent herpes infections in rodents

Scientists report a small molecule called IM-250 can treat active and latent herpes infections in guinea pigs. While there are several drugs that treat active herpes infections, none treat latent herpes simplex virus (HSV), which causes repeated symptoms in about 30% of people with the disease.

HSV causes cold sores, genital herpes, and an inflammation of the cornea known as keratitis. The virus can also cause a life-threatening swelling of the brain in newborns and in immunocompromised people. In 2016, the World Health Organization estimated that 67% of people under age 50 were infected with HSV type 1 (HSV-1), and 13% of people aged 15–59 were infected with HSV type 2 (HSV-2).

All the drugs on the market for HSV work by inhibiting the virus’s DNA polymerase, which builds the virus’s DNA. But those drugs don’t fight latent HSV, which can remain dormant in a person’s neurons until stimuli like UV light or stress cause the symptoms to reemerge.

IM-250 targets a different enzyme, helicase-primase, which HSV uses to unwind DNA as it replicates itself (Sci. Transl. Med. 2021, DOI: 10.1126/scitranslmed.abf8668). IM-250 is not the first compound to take aim at this target, says Gerald Kleymann, founder and CEO of Innovative Molecules, the company that spearheaded the development of IM-250. Pritelivir, a small molecule in Phase 2/3 clinical trials for drug-resistant HSV, also targets helicase-primase. But that molecule, which has been in development for nearly 20 years, has off-target effects that have been attributed to the molecule’s sulfonamide group.

Innovative Molecules’ chemist Christian Gege hypothesized that swapping the sulfonamide for a sulfoximine might eliminate those off-target effects. Chemists at the company also tweaked an aromatic group on pritelivir to make their drug candidate more likely to enter the central nervous system (CNS), where it could go after latent HSV. The resulting compound, IM-250, prevented death in mice given lethal doses of HSV-1. In guinea pigs, IM-250 reduced symptoms of HSV-2 infection and prevented the disease from recurring, even after the rodents were no longer taking the compound.

Christine M. Johnston, a clinical virologist at the University of Washington, notes that there hasn’t been an HSV drug with a new mechanism of action approved in about 40 years. “IM-250 is particularly interesting since it was elegantly optimized to increase potency and penetration into the CNS as well as safety,” she says in an email. She adds that it will be important to determine if the results Kleymann’s group found in guinea pigs can be replicated in people.

Kleymann anticipates that IM-250 will begin Phase 1 clinical trials in late 2022 or early 2023.