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Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.

ABSTRACT: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the immunocompromised, yet no efficient therapeutic exists. We have identified the AVG class of allosteric inhibitors of RSV RNA synthesis. Here, we demonstrate through biolayer interferometry and in vitro RNA-dependent RNA polymerase (RdRP) assays that AVG compounds bind to the viral polymerase, stalling the polymerase in initiation conformation. Resistance profiling revealed a unique escape pattern, suggesting a discrete docking pose. Affinity mapping using photoreactive AVG analogs identified the interface of polymerase core, capping, and connector domains as a molecular target site. A first-generation lead showed nanomolar potency against RSV in human airway epithelium organoids but lacked in vivo efficacy. Docking pose-informed synthetic optimization generated orally efficacious AVG-388, which showed potent efficacy in the RSV mouse model when administered therapeutically. This study maps a druggable target in the RSV RdRP and establishes clinical potential of the AVG chemotype against RSV disease.

SUBMITTER: Sourimant J

PROVIDER: S-EPMC9232112 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.

Sourimant Julien J Lieber Carolin M CM Yoon Jeong-Joong JJ Toots Mart M Govindarajan Mugunthan M Udumula Venkata V Sakamoto Kaori K Natchus Michael G MG Patti Joseph J Vernachio John J Plemper Richard K RK

Science advances 20220624 25

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the immunocompromised, yet no efficient therapeutic exists. We have identified the AVG class of allosteric inhibitors of RSV RNA synthesis. Here, we demonstrate through biolayer interferometry and in vitro RNA-dependent RNA polymerase (RdRP) assays that AVG compounds bind to the viral polymerase, stalling the polymerase in initiation conformation. Resistance profiling revealed a unique escape patt ...[more]

PMID: 35749502

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Project description:ObjectivesRespiratory Syncytial Virus (RSV) is a leading cause of death and hospitalization among infants and young children. People with an immunocompromised status are also at risk for severe RSV infection. There is no specific treatment for RSV infection available. Ribavirin, an antiviral drug approved for severe lung infection by RSV, has shown limited clinical efficacies with severe side effects. Additionally, given the genetic variability of RSV genomes and seasonal change of different strains, a broad-spectrum antiviral drug is highly desirable. The RNA-dependent RNA polymerase (RdRp) domain is relatively conserved and indispensable for the replication of the virus genome and therefore serves as a potential therapeutic target. Previous attempts to identify an RdRp inhibitor have not been successful due to lack of potency or high enough blood exposure. DZ7487 is a novel orally available small molecule inhibitor specifically designed to target the RSV RdRp. Here we present our data showing that DZ7487 can potently inhibited all clinical viral isolates tested, with large safety margin predicted for human.MethodsHEp-2 cells were infected by RSV A and B. Antiviral activities were assessed by in vitro cytopathic effect assay (CPE) and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). DZ7487 antiviral effects in lower airway cells were evaluated in A549 and human small airway epithelial cells (SAEC) cells. DZ7487 induced RSV A2 escape mutations were selected through continuous culture with increasing DZ7487 concentrations in the culture medium. Resistant mutations were identified by next generation sequencing and confirmed by recombinant RSV CPE assays. RSV infection models in both BALB/c mice and cotton rats were used to evaluate DZ7487 in vivo antiviral effects.ResultsDZ7487 potently inhibited viral replication of all clinical isolates of both RSVA and B subtypes. In lower airway cells, DZ7487 showed superior efficacy than the nucleoside analog ALS-8112. Acquired resistant mutation was predominantly restricted at the RdRp domain resulting asparagine to threonine mutation (N363T) of the L protein. This finding is consistent with DZ7487's presumed binding mode. DZ7487 was well tolerated in animal models. Unlike fusion inhibitors, which can only prevent viral infection, DZ7487 potently inhibited RSV replication before and after RSV infection in vitro and in vivo.ConclusionsDZ7487 demonstrated potent anti-RSV replication effect both in vitro and in vivo assays. It has the desired drug-like physical properties to be an effective orally available anti-RSV replication drug with broad spectrum.

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Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.

Publications

Orally efficacious lead of the AVG inhibitor series targeting a dynamic interface in the respiratory syncytial virus polymerase.

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