A new study reveals that the conformation of herpes simplex virus (HSV) polymerase plays a crucial role in the development of drug resistance. The research, employing cryogenic electron microscopy (cryo-EM), provides insights into how mutations in the viral polymerase affect its interaction with antiviral drugs like acyclovir and foscarnet, potentially paving the way for new therapeutic strategies.
Understanding HSV Polymerase and Drug Resistance
HSV, affecting over half the world's population, can cause mild symptoms like oral blisters but also severe complications, including brain infections. Acyclovir and foscarnet, the primary antiviral drugs against HSV, target the viral polymerase, an enzyme essential for viral DNA replication. Resistance to these drugs often arises from mutations in the polymerase.
Jonathan Abraham, a virologist at Harvard Medical School, explained, "Although most people think of herpesviruses as causing cold sores, they can lead to severe brain infections. Severe cases I’ve seen as a doctor have always had me thinking, ‘What can we do in the lab?’"
Cryo-EM Reveals Polymerase Dynamics
Researchers used cryo-EM to observe the HSV polymerase's structure and movements in the presence of DNA and antiviral drugs. Polymerases are often described as "hand-shaped," with fingers, a thumb, and a palm. The study revealed that the polymerase transitions between "open" and "closed" conformations, with the fingers moving towards the palm during DNA replication.
The study found that resistance mutations influenced the movement of the polymerase's fingers rather than the drug-binding site itself. Acyclovir exposure resulted in the same closed conformation as when a nucleotide was in the active site, consistent with its mechanism of blocking viral DNA elongation. Foscarnet also trapped the polymerase in a closed conformation. However, simulations showed that mutations increasing finger dynamics or decreasing drug binding strength allowed the virus to overcome the drugs' blocking effects.
Implications for Future Drug Development
"It’s not necessarily the shape of the hand or where the drug binds that determines resistance," Abraham noted. "Rather, it’s differences in how these enzymes move." The study suggests that future drugs designed to trap HSV polymerase in a static conformation could be effective in combating treatment resistance.
Adrian Wildfire, a virologist and drug development specialist at IQ-IDM, who was not involved in the research, commented, "Polymerase resistance via protein changes is a common way of avoiding drug potency. Will this knowledge drive new drugs for HSV? It already has for HIV and, to some extent, SARS-CoV-2. The lack of alternatives to treat disease brings about better drugs and vaccines."
Limitations and Future Directions
The study's limitations include the inability to compare the effects of different mutations comprehensively. Abraham noted that in real-world scenarios, resistance is rarely absolute, and the implications of varying degrees of inhibition remain unclear.
Currently, predicting treatment resistance through molecular modeling is too complex for clinical use. Abraham suggests that algorithms capable of accurately predicting protein movement are needed to forecast resistance in clinical settings, potentially enabling personalized treatment strategies.
