A German-American team of researchers has developed a compound that could affect latent herpes simplex virus (HSV) infections, reducing the risk of recurrence even after an infection had fully established itself in its neuronal reservoir.

"The long-lasting opinion that herpes cannot be effectively treated – I think we can break this dogma," Gerald Kleyman told BioWorld Science. To date, "when latency has been fully established, then nobody was able to influence the reservoir or recurrent disease."

Kleyman is co-founder and CEO of the startup Innovative Molecules, which is developing new treatments for HSV. The company announced earlier in June that it had closed a EUR 20 million (USD 23.8 million) series A equity financing round led by Life Sciences Partners.

The compound developed by Kleyman and his colleagues, IM-250, was able to reduce both the likelihood of recurrence, and HSV-2 shedding in the off-treatment period.

Most of the time, most HSV infections are asymptomatic. But HSV-2, the main cause of genital herpes, affects half a billion individuals globally, and HSV-1, which primarily causes oral herpes, several billion.

Mild as most infections may be, HSV is a major public health problem. Infection with HSV is a risk factor for contracting HIV, human papilloma virus (HPV), and possibly Alzheimer's disease (AD) – though Kleymann cautioned that the link between HSV and AD is "highly speculative at this moment."

The HSV reservoir differs from typical viral reservoirs, which are established in cells that are capable of dividing. HIV's major reservoir, for example, is T cells.

But herpesvirus can enter adult neurons, which do not divide, under cover from the mucocutaneous surface, where replication takes place, and return to the mucocutaneous surface for recurrent outbreaks.

The mucocutaneous surface, Kleymann said, is the viral "port of entry – that's why it's always at the same place, where recurrence takes place."

Nucleoside analogue acyclovir and related drugs can treat acute infections. But, Kleymann said, "no one has been able to get to the reservoirs" that the virus establishes in neuronal populations, and that seed recurrent outbreaks in about a third of infected individuals.

IM-250 is a helicase-primase inhibitor, which prevents orderly unwinding and preparation of viral DNA for replication. The quinolone antibiotics such as Cipro (ciprofloxacin) use the equivalent approach against bacterial helicases.

Inhibiting helicases in HSV infections was first described as an alternative strategy nearly 20 years ago – with Kleymann, who was working at Bayer at the time, as first author on one of two back-to-back publications in Nature Medicine. The paper by Kleymann and his colleagues reported screening roughly 450,000 small molecules, and identifying what would become pritelivir (Aicuris).

A commentary published at the time asserted that "if helicase-primase drugs inhibit HSV infections more effectively than nucleoside analogues and exhibit safety parameters comparable with acyclovir, they would represent a major advance in controlling HSV infections. Despite the potential promise of these new drugs, however, neither they nor the nucleoside analogues can eliminate virus in the latent state. Consequently, continuation of the HSV pandemic is anticipated and efforts to develop vaccines and novel therapies aimed at eliminating latent virus are still warranted."

Aicuris is preparing to go into pivotal trials with pretalivir, and the investigational drug is available in Germany under a compassionate use program for immunocompromised patients with acyclovir-resistant HSV infections.

In the work described in Science Translational Medicine, Kleymann and his colleagues developed a new chemical class of helicase-primase inhibitors that do not have the same off-target activities as pretalivir. IM-250 also has good brain penetration, which is why it has, "uniquely, sufficient target tissue exposure to appreciably attenuate, if not making infections of neurotrophic herpes simplex viruses become treatable even when they have established life-long latency after primary infection," the authors wrote. As Kleymann put it, the approach is "tackling the virus on its home ground."

That target tissue exposure means that the most serious forms of herpes infection, neonatal herpes and herpes encephalitis, could be susceptible to IM-250 – a possibility the company plans to explore in clinical trials.