Patel, Trushar
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Browsing Patel, Trushar by Subject "Circular DNA"
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- ItemDevelopment of a single-domain antibody to target a G-quadruplex located on the hepatitis B virus covalently closed circular DNA genome(American Society for Microbiology, 2024) Figueroa, Gerardo B.; D'souza, Simmone; Pereira, Higor S.; Vasudeva, Gunjan; Figueroa, Sara B.; Robinson, Zachary E.; Badmalia, Maulik D.; Meier-Stephenson, Vanessa; Corcoran, Jennifer A.; van Marle, Guido; Ni, Yi; Urban, Stephan; Coffin, Carla S.; Patel, Trushar R.To achieve a virological cure for hepatitis B virus (HBV), innovative strategies are required to target the covalently closed circular DNA (cccDNA) genome. Guanine-quadruplexes (G4s) are a secondary structure that can be adopted by DNA and play a significant role in regulating viral replication, transcription, and translation. Antibody-based probes and small molecules have been developed to study the role of G4s in the context of the human genome, but none have been specifically made to target G4s in viral infection. Herein, we describe the development of a humanized single-domain antibody (S10) that can target a G4 located in the PreCore (PreC) promoter of the HBV cccDNA genome. MicroScale Thermophoresis demonstrated that S10 has a strong nanomolar affinity to the PreC G4 in its quadruplex form and a structural electron density envelope of the complex was determined using Small-Angle X-ray Scattering. Lentiviral transduction of S10 into HepG2-NTCP cells shows nuclear localization, and chromatin immunoprecipitation coupled with next-generation sequencing demonstrated that S10 can bind to the HBV PreC G4 present on the cccDNA. This research validates the existence of a G4 in HBV cccDNA and demonstrates that this DNA secondary structure can be targeted with high structural and sequence specificity using S10.
- ItemHost transcription factors in hepatitis B virus RNA synthesis(MDPI, 2020) Turton, Kristi L.; Meier-Stephenson, Vanessa; Badmalia, Maulik D.; Coffin, Carla S.; Patel, Trushar R.The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.