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Structure-guided functional analysis of the hepadnaviral polymerase

Award Number: R01AI198338
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/18/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Structure-guided functional analysis of the hepadnaviral polymerase - Hepadnaviruses are partially double-stranded DNA viruses that replicate by protein-primed reverse transcription. This family includes duck hepatitis B virus (DHBV) with which hepadnaviral reverse transcription was discovered and human hepatitis B virus (HBV) that kills 1,100,000 people annually. HBV therapy primarily employs nucleos(t)ide analog drugs that target the viral reverse transcriptase (RT) activity. Reverse transcription is catalyzed by the 4-domain viral polymerase (P) which has protein priming, RT, and ribonuclease H (RNase H) activities. The TP and spacer domains are unique to the hepadnaviruses. Reverse transcription starts with chaperone-mediated binding of P to the ε stem loop on the viral pregenomic RNA (pgRNA). Reverse transcription is primed by a tyrosine in P’s terminal protein domain (TP), templated by ε. The RT synthesizes the first strand of the viral DNA, and the RNase H destroys the pgRNA to permit synthesis of the second DNA strand. P is a monomer, and the covalent linkage between P and the DNA persists throughout reverse transcription. Hepadnaviral protein-primed reverse transcription differs greatly from retroviral reverse transcription, but its enzymology is poorly understood even though HBV P is a major drug target. This knowledge gap is in part due to the inability to determine the structure of P. We recently predicted the structure of P and validated the model. This revealed a novel fold in which the TP domain that primes reverse transcription is cupped over P’s catalytic core of P, with the priming tyrosine on a loop over the RT active site. This model makes mechanistic predictions regarding reverse transcription and provides guidance for how to test the hypotheses. Premise: The molecular model of P enables in-depth mechanistic analyses of P structure, nucleic acid binding, and DNA priming by the enzyme for the first time. Aim 1. What P sequences are needed for ε binding and priming? We will define the minimal active form(s) of P for RNA binding and DNA priming, and identify residues of P that contact ε and are essential for priming. Aim 2. What are the structural alterations to P associated with the shift from the priming-incompetent to priming-competent state? We will define how the TP domain binds to the catalytic core of P, explore P’s conformational shifts during priming, and determine how key RNA binding motifs are exposed during ε binding. Aim 3. How do conformational dynamics of P contribute to ε binding and priming? We will probe how P’s flexibility affects ε binding and DNA priming using molecular dynamics plus pharmacological and mutational analyses. We will test effects of mutations affecting RNA binding and DNA priming on viral replication in cells. This study will fill major gaps in our understanding of hepadnaviral reverse transcriptase enzymology by defining the interactions holding P in its novel conformation, how P binds to ε, and how enzyme flexibility contributes to the early phases of reverse transcription. It will also provide key information needed to develop non-active site inhibitors of HBV P to improve therapy for HBV patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $627,222 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	1	5/19/2026	NEW	$627,222
														Subtotal = $627,222

Grand Total All Awards = $627,222

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Structure-guided functional analysis of the hepadnaviral polymerase

Award Number: R01AI198338

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/18/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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