Cytomegalovirus (CMV) is related to the viruses that cause chickenpox and mononucleosis. Between 50 percent and 80 percent of U.S. adults are infected by CMV by age 40. Most don’t get sick or even know they are infected, but CMV is a major threat to infants and to those with compromised immune systems, especially bone marrow and organ transplant patients. The virus spreads through close contact with body fluids, and once in the body, stays there for life. Transmission from mother to infant occurs in about 40,000 U.S. births each year, and about 10 percent of infected babies die or have severe problems as newborns. Many more have hearing loss or developmental problems later in life. Current anti-CMV agents have severe side effects, such as liver and bone marrow toxicity, so better treatments are needed. These investigators are developing a medication that may inhibit CMV activity but also may be effective against related viruses with few treatment options.
Scientific Synopsis
CMV infection is a major health concern in the immunocompromised population, especially among recipients of bone marrow and solid organ transplants. The current standard for therapy is ganciclovir (GCV) and its prodrug valGCV, but both can cause bone-marrow toxicity, severe neutropenia and emerging resistance. Alternatives include foscarnet (PFA) and cidofovir, but nephrotoxicity limits their use. Therefore, there is still a major unmet medical need for new anti-CMV agents. Researchers in the laboratory of Jiri Zemlicka, Ph.D., at Wayne State University identified a novel series of purine nucleoside analogs, the methylenecyclopropanes, and showed they are potent inhibitors of human CMV. A second-generation analog, ZSM-I-62, now has been shown to be very potent against murine and human CMV, including GCV- and PFA-resistant clinical isolates, and is less toxic to human bone marrow cells. ZSM-I-62 may offer a promising alternative that has broad activity across members of the beta- and gamma-herpesviruses, for which few therapeutic options exist.
The project goal is to complete the ZSM-I-62 preclinical toxicology and safety pharmacology studies, file an Investigational New Drug (IND) application for the treatment of CMV-mediated disease and initiate a human clinical phase I safety evaluation. The requested BrIDGs ZSM-I-62 synthetic route improvements, bulk Good Manufacturing Practice (GMP)-grade synthesis and formulation support will greatly facilitate this goal.
Lead Collaborator
Wayne State University School of Medicine, Detroit
Jiri Zemlicka, Ph.D.
Public Health Impact
CMV infection continues to be a major cause of morbidity and mortality in immune-suppressed patients, especially recipients of solid organ or bone marrow transplants. The five drugs that have been approved for use in patients with CMV infection have severe limitations that preclude their long-term use. These include poor oral bioavailability, dose-related toxicity and selection of drug-resistant viral mutants. Therefore, there is an urgent medical need for more effective and safer therapies.
Outcomes
Work on this project is complete. The investigator successfully filed an IND application using BrIDGs data.
Project Details
- Synthesis of GMP and non-GMP material
- Formulation development