Hi everyone! My name is Holly Walden, and I am a PhD graduate student in the lab of Dr. John Tavis at Saint Louis University, School of Medicine in St. Louis, MO USA. My role in the lab is to perform biological and pharmacological evaluations on novel HBV RNase H inhibitors.
Currently, treatments for chronic HBV infections are capable of suppressing HBV in most patients. However, once an individual stops treatment, viral replication starts to rebound. The goal of our lab is to identify therapies that will target new areas of HBV replication that can be combined with therapies for other targets to either decrease or completely stop viral replication. The primary focus of the Tavis lab is on the HBV polymerase (P) which is responsible for HBV DNA replication through reverse transcription. The HBV polymerase has two domains that catalyze reverse transcription, the reverse transcriptase (RT) domain and the ribonuclease H (RNase H) domain. The RT domain, which is the target for nucleos(t)ide analogs, is responsible for creating DNA from an RNA template. The primary target for the Tavis lab is the RNase H domain, which degrades the viral RNA allowing for the second strand of viral DNA to be synthesized. Currently, there are no drugs targeting the RNase H despite it being a promising drug target. This is due in part to the fact that assays necessary for screening RNase H inhibitors have only recently been developed.
Our lab is collaborating with medicinal chemists to synthesize novel HBV RNase H inhibitors, and it is my job to screen them to find promising candidates. Currently, our lab has identified the N-hydroxypyridinedione (HPD) chemotype as having some of the most potent inhibitors yet identified. We are exploring a novel HPD derivative series designed to overcome stability issues present with some of the earlier HPD compound series that shows substantial promise. My primary role in the lab has been to screen these compounds for their effectiveness at inhibiting HBV replication and their toxicity to cells. Several compounds have been found to inhibit HBV replication at low concentrations and minimal cytotoxicity, which is being addressed with collaborators.
My current goal is to screen these compounds for their pharmacological properties which involves evaluation of drug absorption, metabolism, distribution, and excretion (ADME). I have screened all compounds for their solubility limits and apparent passive permeability rates. These assays are necessary to ensure compounds are soluble at physiologically relevant pHs as well as permeable to ensure they are being absorbed to be delivered to the site of action, the liver. Several of the compounds screened thus far have shown to be soluble and permeable. My next goal will be evaluating the compounds for their potential to inhibit the most significant cytochrome P450 enzymes, an important family of enzymes responsible for the vast majority of drug metabolism in the liver.
I am very excited about the promise this novel class of HPDs has and I am looking forward to being able to screen them in more in-depth assays that will allow our lab to determine if any are promising enough to move into preclinical development.
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