Researchers from the University of Connecticut School of Medicine and School of Pharmacy say they have published an article (“Two-Metal Ion-Dependent Enzymes as Potential Antiviral Targets in Human Herpesviruses”) in mBio that could open the door to a novel approach to attacking herpesviruses. The study demonstrated that targeting two-metal ion-dependent enzymes of human herpesviruses with two compounds, AK-157 and AK-166, can inhibit the replication of the virus. The finding provides new opportunities to developing agents against herpesviruses, according to the scientists.

“A lot of people know the herpes simplex viruses, but there is actually a family of nine different herpesviruses including cytomegalovirus (CMV) which causes a lot of problems for immunocompromised people, folks getting transplants and chemotherapy patients for example. We need better therapeutic agents that can be used in these very vulnerable populations,” noted co-author of the study Dennis Wright, PhD, professor of medicinal chemistry in the School of Pharmacy at the University of Connecticut. “Right now, the therapeutic agents that are out there aren’t terribly effective in terms of being able to treat all the viruses, and many of them have a significant dose-limiting toxicities and associated side effects.”

Looking for one drug

Ideally, said Wright, there would be one drug that would inhibit the reactivation of all nine of the herpesviruses. Co-study author Sandra K. Weller, PhD, a distinguished professor of molecular biology and biophysics in the School of Medicine at the University of Connecticut, identified targets that would allow just that. She identified herpesvirus enzymes that require two magnesiums for the herpesvirus to replicate.

“The majority of drug discovery efforts against herpesviruses has focused on nucleoside analogs that target viral DNA polymerases [agents that are associated with dose-limiting toxicity and/or a narrow spectrum of activity],” she explained. We are pursuing a strategy based on targeting two-metal-ion-dependent (TMID) viral enzymes.”

“This family of enzymes consists of structurally related proteins that share common active sites containing conserved carboxylates predicted to coordinate divalent cations essential for catalysis. Compounds that target TMID enzymes, such as HIV integrase and influenza endoribonuclease, have been successfully developed for clinical use. HIV integrase inhibitors have been reported to inhibit replication of herpes simplex virus (HSV) and other herpesviruses; however, the molecular targets of their antiviral activities have not been identified,” write the investigators.

“We employed a candidate-based approach utilizing several two-metal-directed chemotypes and the potential viral TMID enzymatic targets in an effort to correlate target-based activity with antiviral potency. The panel of compounds tested included integrase inhibitors, the anti-influenza agent baloxavir, three natural products previously shown to exhibit anti-HSV activity, and two 8-hydroxyquinolines (8-HQs), AK-157 and AK-166, from our in-house program.

“The integrase inhibitors exhibited weak overall anti-HSV-1 activity, while the 8-HQs were shown to inhibit both HSV-1 and cytomegalovirus (CMV). Target-based analysis demonstrated that none of the antiviral compounds acted by inhibiting ICP8, contradicting previous reports. On the other hand, baloxavir inhibited the proofreading exonuclease of HSV polymerase, while AK-157 and AK-166 inhibited the alkaline exonuclease UL12.

“In addition, AK-157 also inhibited the catalytic activity of the HSV polymerase, which provides an opportunity to potentially develop dual-targeting agents against herpesviruses.”

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