Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein

Patel, Ruchin; Murray, Edward; Nahas, Debbie D.; Yazdani, Mahdieh; Ambler, Brett; Murgolo, Nicholas; Howe, John A.

doi:10.3390/pathogens15010085

Open AccessArticle

Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein

by

Ruchin Patel

^*,

Edward Murray

,

Debbie D. Nahas

,

Mahdieh Yazdani

,

Brett Ambler

,

Nicholas Murgolo

^*

and

John A. Howe

Merck & Co., Inc., Rahway, NJ 07065, USA

^*

Authors to whom correspondence should be addressed.

Pathogens 2026, 15(1), 85; https://doi.org/10.3390/pathogens15010085

Submission received: 1 December 2025 / Revised: 7 January 2026 / Accepted: 10 January 2026 / Published: 13 January 2026

(This article belongs to the Special Issue Structural Biology for Virus Research)

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Abstract

Respiratory syncytial virus (RSV) remains a leading cause of lower respiratory tract infections (LRTIs) and infant mortality worldwide. Despite recent advances in prophylactic interventions, effective therapeutics for active RSV infection are still lacking. Small molecule non-nucleoside inhibitors (NNIs) targeting the RSV L protein, particularly its polyribonucleotidyltransferase (PRNTase) domain, represent a promising antiviral strategy. Here, we evaluate the genetic variability of the PRNTase domain and the binding pocket of two NNIs, MRK-1 and MRK-2, to assess the potential for preexisting resistance. A comprehensive analysis of 28,140 RSV L protein sequences from NCBI Virus and GISAID EpiRSV databases revealed low overall variability within the PRNTase domain and near-complete conservation of the MRK-1/2 binding pocket. Resistance-associated mutations identified through in vitro dose-escalation studies localized to this pocket but were absent in global sequence datasets. These findings support the PRNTase domain as a genetically stable and viable target for NNI-based RSV therapeutics and suggest a low likelihood of preexisting resistance among circulating strains.

Keywords: RSV; polymerase; PRNTase; MRK-1; NNI; resistance; surveillance

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MDPI and ACS Style

Patel, R.; Murray, E.; Nahas, D.D.; Yazdani, M.; Ambler, B.; Murgolo, N.; Howe, J.A. Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein. Pathogens 2026, 15, 85. https://doi.org/10.3390/pathogens15010085

AMA Style

Patel R, Murray E, Nahas DD, Yazdani M, Ambler B, Murgolo N, Howe JA. Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein. Pathogens. 2026; 15(1):85. https://doi.org/10.3390/pathogens15010085

Chicago/Turabian Style

Patel, Ruchin, Edward Murray, Debbie D. Nahas, Mahdieh Yazdani, Brett Ambler, Nicholas Murgolo, and John A. Howe. 2026. "Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein" Pathogens 15, no. 1: 85. https://doi.org/10.3390/pathogens15010085

APA Style

Patel, R., Murray, E., Nahas, D. D., Yazdani, M., Ambler, B., Murgolo, N., & Howe, J. A. (2026). Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein. Pathogens, 15(1), 85. https://doi.org/10.3390/pathogens15010085

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

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Structural Mapping of Surveillance Data Reveals Conservation of NNI Binding Site in RSV L Protein

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