Inhibition of Human Herpesviruses

Novel therapeutic agents for herpes simplex and cytomegaloviruses

Viruses from the human herpesvirus family are estimated to infect 90% of the adult population worldwide, and are responsible for lifelong debilitating and cogenital infections. Some members of this family are associated with human cancers and age-related cognitive decline.

Using our expertise in small molecule drug discovery and development in infectious disease, QMD is leveraging decades of HSV genetic and biochemical research to identify, characterize and exploit multiple drug targets of human herpesviruses.

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The human herpesviruses are responsible for lifelong debilitating and congenital infections...

for lifelong debilitating and congenital infections, significant infection risk in immunocompromised patients, and elevated risk of developing viral-associated malignancies. The herpesvirus family is comprised of three major classes: alpha, beta and gamma that diverge in tissue tropism and many aspects of their interactions with their hosts.

The human alpha herpesviruses include human herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). HSV infections are one of the most widespread infectious diseases in the world, affecting between 60 and 95% of the population. HSV-1 and -2 are associated with a wide range of clinical manifestations including cold sores, genital lesions, kerititis, corneal blindness, encephalitis and severe neonatal infections. VZV causes chickenpox and shingles, but can also be associated with viral encephalitis and a painful condition known as postherpetic neuralgia.

The human beta herpesviruses, HCMV, is associated with mononucleosis, retinitis, pneumonia, CNS disease and hepatitis in immunocompetent individuals; however, HCMV can cause significant morbidity and mortality especially in patients who receive a hematopoetic stem cell or a solid organ transplant. HCMV infection during pregnancy is an important cause of disseminated neonatal infection with significant morbidity in infants.

The gamma herpesviruses include Epstein-Barr virus (EBV) and Kaposis sarcoma associated herpesvirus (KSHV). These viruses are associated with diseases including mononucleosis and malignancies such as B-cell lymphomas, nasopharyngeal carcinoma and Kaposis Sarcoma. Kaposis Sarcoma is now recognized as one of the most common cancers in many sub-Saharan African countries. Human herpesviruses are associated with significant disease, underscoring the need for safe and effective antiviral strategies.

Despite the wide-spread nature of these viral pathogens, there are relatively few classes of safe and effective therapeutics in clinical use.

DNA polymerase inhibitors, most notably the nucleoside analog acyclovir and its prodrug valacyclovir (Valtrex), are the mainstay of current therapies. While Valtrex is very effective for managing HSV1/2 in immunocompetent individuals, there is a sharp increase in the onset of resistance in immunocompromised patients leading to frequent and severe reactivations. Valtrex is less active against VZV than HSV but remains the first-line treatment option for this indication. EBV, KSHV and CMV are far less sensitive to the action of Valtrex and as such it is rarely used to treat these infections. The poor responsiveness of CMV and other viruses to acyclovir led to the development of the more potent polymerase inhibitors ganciclovir/valganciclovir that are used for both prophylaxis and lytic CMV infections.However, this use of these agents in patients is often discontinued because of high cytotoxicity. Foscarnet is an injectable non-nucleoside antiviral that is often the recommended second-line agent but also suffers dose-limiting nephrotoxicity and its use is often discontinued.

While there are a handful of other nucleoside analogs, these often do not have a desirable safety and efficacy profile and are only narrowly used. There is clearly a compelling need for the development of safer and more efficacious agents to treat these wide-spread viral pathogens.

Existing strategies for development of new herpesvirus therapies have focused on individual viral targets such as the viral polymerase. As noted above, QMD is focused on developing therapeutic agents based on multi-targeting strategies. This strategy will be employed in two ways:

  1. Design and test multi-targeting small molecule inhibitors that are expected to inhibit two or more essential proteins in one virus (HSV); and
  2. Design and test broad spectrum small molecule inhibitors that have the potential to inhibit the same target in several human herpesviruses.

Inhibition of two or more viral proteins with one compound

Despite differences between the three classes of human herpesviruses, the mechanisms by which they replicate their DNA during productive (lytic) infection are largely conserved. Viral enzymes involved in DNA replication have provided a rich store of useful targets for antiviral therapy. The NIH has awarded QMD funding for our proposal that focuses on the development of multi-targeting inhibitors that block two or more HSV proteins that fall into the nucleotidyltransferase superfamily (NTS). This approach is expected to lead to the production of antivirals that are less susceptible to the development of mutation-based resistance. Combination therapy in which patients are treated with multiple drugs against different targets is a well-established way to decrease resistance; however, our approach has the advantage that the pharmacokinetics and toxicity will be much easier to manage with only one drug.

HSV encodes three essential NTS proteins that are characterized by the presence of an acidic catalytic triad: viral single strand DNA binding protein (ICP8), viral terminase (UL15) and viral alkaline nuclease (UL12). Small molecule inhibitors that bind at this catalytic triad are hypothesized to exhibit potent inhibition of at least two of the proteins. As part of this project, QMD will prepare lead-like, dual metal-directed chemotypes that are expected to inhibit one or more of the HSV NTS proteins. These novel compounds will be tested for efficacy in biochemical assays and for reduction of virus production.

Pan-Herpes inhibitors that inhibit HSV, CMV and other members of the herpesvirus family

QMD seeks to develop broad spectrum anti-herpesviral therapeutics by targeting viral enzymes that are extremely well conserved between all members of the herpesvirus family. Existing antivirals inhibit the viral polymerase and show narrow specificity for viral inhibition. One of the most conserved proteins across species of herpesviruses, however, is the viral nuclease (UL12 in HSV, UL98 in CMV, BGLF5 in EBV, and SOX in KSHV). We have begun working on the UL98 protein of CMV through a project funded by Connecticut Innovations through the PITCH program. The Yale discovery Center is currently performing a high throughput screen against the UL98 protein that we expressed at the Protein Expression Core at UConn Health.

Current goals:

  • Prepare lead-like, dual metal-directed chemotypes as multi-target inhibitors of HSV and HCMV proteins.
  • Test lead compounds for efficacy in biochemical assays for HSV proteins ICP8, UL12, and UL15 activity and for reduction of HSV infectivity.
  • In parallel, test lead compounds for efficacy in biochemical assays for HCMV.

We anticipate the identification of multiple lead scaffolds that target two or more of the above viral targets and exhibit antiral activity. Upon completion of these goals, we will be well-positioned to pursue further development of novel antiviral agents for treatment of HSV and HCMV infections.