Resistance profiles for the investigational neuraminidase inhibitor AV5080 in influenza A and B viruses.

Antiviral Res

ChemDiv, 12760 High Bluff Drive, Ste. 370 San Diego, CA, 92130, USA; AVISA LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, FL, 33009, USA. Electronic address:

Published: September 2023

Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A(H1N1)pdm09, A(H3N2), A(H5N1), and A(H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119G/V, NA-H274Y, NA-I122L/N, and NA-R150K. Broadly, AV5080 showed enhanced in vitro efficacy when compared with oseltamivir and/or zanamivir. Reduced AV5080 inhibition was determined for influenza A viruses with NA-E119G and NA-R292K, and for B/Victoria-lineage viruses with NA-I122N/L and B/Yamagata-lineage virus with NA-R150K. Molecular modeling suggested loss of the short hydrogen bond to the carboxyl group of AV5080 affected inhibition of NA-R292K viruses, whereas loss of the salt bridge with the guanidine group of AV5080 affected inhibition of NA-E119G. The resistance profiles and predicted binding modes of AV5080 and zanamivir are most similar, but dissimilar to those of oseltamivir, in part because of a guanidine moiety compensatory binding effect. Overall, our data suggests that AV5080 is a promising orally-dosed NAI that exhibited similar or superior in vitro efficacy against viruses with reduced or highly reduced inhibition phenotypes with respect to currently approved NAIs.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528385PMC
http://dx.doi.org/10.1016/j.antiviral.2023.105701DOI Listing

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Resistance profiles for the investigational neuraminidase inhibitor AV5080 in influenza A and B viruses.

Antiviral Res

September 2023

ChemDiv, 12760 High Bluff Drive, Ste. 370 San Diego, CA, 92130, USA; AVISA LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, FL, 33009, USA. Electronic address:

Neuraminidase inhibitors (NAIs) are recommended for influenza treatment and prevention worldwide. The most widely prescribed NAI is oral oseltamivir, while inhaled zanamivir is less commonly used. Using phenotypic neuraminidase (NA) enzymatic assays and molecular modeling approaches, we examined the ability of the investigational orally-dosed NAI AV5080 to inhibit viruses of the influenza A(H1N1)pdm09, A(H3N2), A(H5N1), and A(H7N9) subtypes and the influenza B/Victoria- and B/Yamagata-lineages containing NA substitutions conferring oseltamivir or zanamivir resistance including: NA-R292K, NA-E119G/V, NA-H274Y, NA-I122L/N, and NA-R150K.

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Article Synopsis
  • Clade 2.3.4.4b HPAI A(H5N1) viruses have shown potential drug resistance, with about 0.8% of analyzed strains exhibiting markers for resistance to FDA-approved antivirals, indicating a possible public health threat.
  • Testing revealed that most of these viruses remain susceptible to existing antivirals, particularly favoring investigational options like AV5080 over conventional treatments.
  • Continued surveillance of these viruses is crucial for understanding their evolution and refining strategies for antiviral stockpiling to mitigate potential health risks.
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