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Updated: Dec 15, 2025
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase
Robert M Cox1, Julien Sourimant1, Mart Toots1
1Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
Abstract:
Paramyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV) are a substantial health threat. In a high-throughput screen for inhibitors of HPIV3 (a major cause of acute respiratory infection), we identified GHP-88309-a non-nucleoside inhibitor of viral polymerase activity that possesses unusual broad-spectrum activity against diverse paramyxoviruses including respiroviruses (that is, HPIV1 and HPIV3) and morbilliviruses (that is, MeV). Resistance profiles of distinct target viruses overlapped spatially, revealing a conserved binding site in the central cavity of the viral polymerase (L) protein that was validated by photoaffinity labelling-based target mapping. Mechanistic characterization through viral RNA profiling and in vitro MeV polymerase assays identified a block in the initiation phase of the viral polymerase. GHP-88309 showed nanomolar potency against HPIV3 isolates in well-differentiated human airway organoid cultures, was well tolerated (selectivity index > 7,111) and orally bioavailable, and provided complete protection against lethal infection in a Sendai virus mouse surrogate model of human HPIV3 disease when administered therapeutically 48 h after infection. Recoverees had acquired robust immunoprotection against reinfection, and viral resistance coincided with severe attenuation. This study provides proof of the feasibility of a well-behaved broad-spectrum allosteric antiviral and describes a chemotype with high therapeutic potential that addresses major obstacles of anti-paramyxovirus drug development.
Insights
A new broad-spectrum antiviral, GHP-88309, inhibits paramyxovirus polymerase activity. This drug candidate shows promise for treating respiratory infections caused by human parainfluenza virus type-3 (HPIV3) and measles virus (MeV).
Area of Science:
- Virology and Antiviral Drug Discovery
- Molecular Biology
- Respiratory Infectious Diseases
Background:
- Paramyxoviruses, including human parainfluenza virus type-3 (HPIV3) and measles virus (MeV), pose significant global health risks.
- HPIV3 is a primary cause of acute respiratory infections, necessitating effective therapeutic interventions.
- Existing antiviral strategies for paramyxoviruses are limited, highlighting the need for novel drug development.
Purpose of the Study:
- To identify and characterize inhibitors of viral polymerase activity in paramyxoviruses.
- To evaluate the broad-spectrum antiviral potential of a novel compound, GHP-88309.
- To investigate the mechanism of action and therapeutic efficacy of GHP-88309 against paramyxovirus infections.
Main Methods:
- High-throughput screening to identify inhibitors of HPIV3 polymerase.
- Resistance profiling and photoaffinity labeling to map the viral polymerase binding site.
- In vitro polymerase assays, viral RNA profiling, and organoid/in vivo infection models to assess antiviral activity and mechanism.
Main Results:
- GHP-88309, a non-nucleoside inhibitor, demonstrated broad-spectrum activity against respiroviruses and morbilliviruses.
- A conserved binding site in the viral L protein was identified, validating GHP-88309's allosteric mechanism.
- GHP-88309 exhibited nanomolar potency, good tolerability, oral bioavailability, and provided complete protection in a mouse model of HPIV3 infection.
Conclusions:
- GHP-88309 represents a promising broad-spectrum allosteric antiviral agent against paramyxoviruses.
- The identified chemotype addresses key challenges in anti-paramyxovirus drug development.
- This study validates the therapeutic potential of targeting viral polymerase initiation for treating paramyxovirus infections.
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