23 Dec New Compound May Suppress Resistant Herpes Simplex
MedicalResearch.com Interview with:
Professors Lynda A. Morrison, Ph.D. and John E. Tavis, Ph.D.
Dept. of Molecular Microbiology and Immunology
Saint Louis University School of Medicine
St. Louis, MO 63104
Medical Research: What is the background for this study? What are the main findings?
Response: A number of viruses use enzymes in the nucleotidyl transferase superfamily (NTS) to carry out their genome replication. These enzymes include the RNaseH and integrase of HIV and the RNaseH of hepatitis B virus (HBV). Herpesviruses also encode proteins with functions that are consistent with NTS enzymes. We therefore tested compounds known or suspected to inhibit the HBV RNaseH for their capacity to reduce herpes simplex virus (HSV)-1 and HSV-2 in cell culture assays. We found that certain compounds from several different chemical families could inhibit HSV replication up to 1 million-fold, and were effective down to concentrations that are already in the same range as existing anti-herpesvirus drugs. Many of the same compounds that inhibited HSV-1 and HSV-2 also inhibited another human herpesvirus, cytomegalovirus. Importantly, we showed that these new inhibitory compounds have a different mechanism of action than acyclovir, a nucleoside analog that is the standard of care. In addition, the new compounds we identified could inhibit the replication of acyclovir-resistant HSV-1 and HSV-2.
Medical Research: What should clinicians and patients take away from your report?
Response: Because the compounds we identified can inhibit viruses resistant to standard nucleoside analog therapy, they may be very useful in combination with the nucleoside analog drugs to completely suppress herpes simplex virus replication. They may also be useful as salvage therapy for patients who have acquired or developed infections with nucleoside analog-resistant mutants.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: We will be further refining the inhibitory capacity of the lead compounds, while altering them to minimize toxicity. Understanding the pharmacokinetic and pharmacodynamic properties of the compounds will also be essential to identifying those with greatest potential utility as drugs. We are also examining the rate at which viral resistance to these new compounds evolves. Our preliminary data suggest resistance develops much more slowly against the NTS inhibitors than it does against acyclovir. This is exciting because it suggests they may be very useful for treatment of herpesvirus infections while minimizing the attendant risk of generating drug-resistant mutants.
E. Tavis, H. Wang, A. E. Tollefson, B. Ying, M. Korom, X. Cheng, F. Cao, K. L. Davis, W. S. M. Wold, L. A. Morrison. Inhibitors of Nucleotidyltransferase Superfamily Enzymes Suppress Herpes Simplex Virus Replication. Antimicrobial Agents and Chemotherapy, 2014; 58 (12): 7451 DOI: 10.1128/AAC.03875-14