Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors

Boyd, Michael J.; Bandarage, Upul K.; Bennett, Hamilton; Byrn, Randal R.; Davies, Ioana; Gu, Wenxin; Jacobs, Marc; Ledeboer, Mark W.; Ledford, Brian; Leeman, Joshua R.; Perola, Emanuele; Wang, Tiansheng; Bennani, Youssef L.; Clark, Michael P.; Charifson, Paul S.

doi:10.1016/j.bmcl.2015.03.013

Cited by 28 publications

(15 citation statements)

References 12 publications

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“…However, one consequence of the extended mid-linker region in PB2long is that residues 520–535 impinge on the PB2 cap-binding site and directly interact with the ligand, thereby revealing new determinants of VX-787 binding. The carboxylic acid of VX-787 was previously shown to be a key contributor to PB2 binding 20 . In the PB2cap/VX-787 complex this moiety is solvent exposed and forms water-mediated interactions with H357, Q406, and R355 (Fig.…”

Section: Resultsmentioning

confidence: 98%

Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

Xie²,

Wartchow

et al. 2017

Sci Rep

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Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11–13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787.

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Section: Resultsmentioning

confidence: 98%

Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

Xie²,

Wartchow

et al. 2017

Sci Rep

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“…A further structure-activity relationship (SAR) exploration with isosteric replacements of the carboxylic group of VX-787 showed that the pKa value and orientation of the negative charge significantly affect both anti-influenza potency and selectivity for unwanted protein kinase targets (the latter being related to compound binding to the ATP site of cellular kinases). 206 VX-787 possesses strong antiviral activity (i.e., EC 50 values in the nanomolar range) in cellular assays with a broad range of influenza A virus strains, including NAI-and amantadine-resistant isolates, 2009 pandemic H1N1, and circulating avian H5N1 strains. 37,207 Its activity against influenza B virus is negligible, which can be attributed to amino acid differences in the PB2-CBD.…”

Section: Inhibitors Of Cap-binding By Pb2mentioning

confidence: 99%

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

138

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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“…This is a novel, non-nucleoside polymerase inhibitor that targets the PB2 subunit of influenza A viruses. Targeting the PB2 avoids docking of the 7-methyl GTP cap structure, thus preventing viral RNA synthesis (Clark et al, 2014; Boyd et al, 2015). The early activity of pimovidir in the cell cycle has shown to improve cell viability compared to oseltamivir (Byrn et al, 2015).…”

Section: Viral Targeting Candidatesmentioning

confidence: 99%

Overview of Current Therapeutics and Novel Candidates Against Influenza, Respiratory Syncytial Virus, and Middle East Respiratory Syndrome Coronavirus Infections

2019

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Emergence and re-emergence of respiratory virus infections represent a significant threat to global public health, as they occur seasonally and less frequently (such as in the case of influenza virus) as pandemic infections. Some of these viruses have been in the human population for centuries and others had recently emerged as a public health problem. Influenza viruses have been affecting the human population for a long time now; however, their ability to rapidly evolve through antigenic drift and antigenic shift causes the emergence of new strains. A recent example of these events is the avian-origin H7N9 influenza virus outbreak currently undergoing in China. Human H7N9 influenza viruses are resistant to amantadines and some strains are also resistant to neuraminidase inhibitors greatly limiting the options for treatment. Respiratory syncytial virus (RSV) may cause a lower respiratory tract infection characterized by bronchiolitis and pneumonia mainly in children and the elderly. Infection with RSV can cause severe disease and even death, imposing a severe burden for pediatric and geriatric health systems worldwide. Treatment for RSV is mainly supportive since the only approved therapy, a monoclonal antibody, is recommended for prophylactic use in high-risk patients. The Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging respiratory virus. The virus was first recognized in 2012 and it is associated with a lower respiratory tract disease that is more severe in patients with comorbidities. No licensed vaccines or antivirals have been yet approved for the treatment of MERS-CoV in humans. It is clear that the discovery and development of novel antivirals that can be used alone or in combination with existing therapies to treat these important respiratory viral infections are critical. In this review, we will describe some of the novel therapeutics currently under development for the treatment of these infections.

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Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors

Cited by 28 publications

References 12 publications

Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Overview of Current Therapeutics and Novel Candidates Against Influenza, Respiratory Syncytial Virus, and Middle East Respiratory Syndrome Coronavirus Infections

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