Student: Kathryn Vollmer, Undergraduate Student in Pharmacy, Drake University
Research Mentor: Dr. Brian Gentry
Activation of Prodrug MBX-2168 to Combat Human Cytomegalovirus
Human cytomegalovirus (HCMV), a beta herpes virus, can cause severe and sometimes fatal complications in immunocompromised or immunosuppressed patients. Previous findings have demonstrated immune dysfunction in astronauts exposed to a microgravity environment for extended periods of time. In addition, astronauts returning from long-term space missions have demonstrated increased titers of HCMV in their bloodstream. Currently, ganciclovir (GCV) is the primary pharmacotherapy option for treatment of systemic HCMV infections. The mechanism of action of GCV starts with viral-specific monophosphorylation followed by phosphorylation to a triphosphate, the active compound that inhibits viral DNA synthesis and replication. However, high incidences of adverse effects (neutropenia) and drug resistance limit the utility of this drug.
MBX-2168, a third-generation methylenecyclopropane nucleoside analog (MCPNA) prodrug, demonstrates broad-spectrum antiviral activity against all members of the herpesvirus family (including HCMV) without any observable increase in adverse effects. MBX-2168 has a similar mechanism of action to GCV with two notable differences. First, MBX-2168 is activated in part or in whole by the cellular kinase TAOK3. Second, the guanine ring of MBX-2168 is enzymatically modified, essentially converting the compound to synguanol (a first-generation MCPNA) intracellularly. We hypothesize that enzymatic removal of a butyl-ether moiety at the 6-position of the guanine ring by adenosine deaminase-like protein 1 (ADAL-1) is an essential step in the activation of this prodrug. Currently, I am conducting research examining the conversion of MBX-2168 to synguanol via ADAL-1. For my experiments, I utilize a custom-made enzyme assay to allow for drug conversion and high-pressure liquid chromatography to measure product formation. I have performed time-based experiments to examine the conversion of drug over time and am currently performing experiments to determine the kinetic constants of conversion. As with any drug, these experiments are necessary to fully understand the mechanism of action of the drug and to assist with the formulation of a dosing regimen. Both of these are critical for an Investigational New Drug application, the first step in moving the drug into clinical trials.