Peramivir conjugates as orally available agents against influenza H275Y mutant
Peng-Cheng Wang1, Din-Chi Chiu1, Jia-Tsrong Jan2
1Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Abstract:
Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both wild-type and H275Y viruses with the IC50 values in nanomolar range. The molecular modeling reveals that the caffeate moiety of conjugate 9 prefers to reside in the 295-cavity of H275Y neuraminidase, thus providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with peramivir, the lipophilicity of conjugates 8 and 9 also increases by incorporation of the caffeate moiety. Thus, conjugates 8 and 9 offer better effect to protect MDCK cells from infection of H275Y virus with low EC50 value (∼17 nM). Administration of conjugates 8 or 9 by oral gavage is effective in treatment of mice that are infected by lethal dose of wild-type or H275Y influenza viruses. Considering drug metabolism, since the ester linkage in conjugate 8 is susceptible to hydrolysis in plasma, conjugate 9 with robust amide linkage may be a better candidate for development into orally available anti-influenza drug that is also active to mutant viruses.
Insights
New peramivir conjugates with caffeic acid show potent activity against wild-type and H275Y influenza viruses. These compounds offer enhanced protection and oral efficacy in mice, with conjugate 9 being a promising candidate for oral anti-influenza drug development.
Area of Science:
- Pharmaceutical Chemistry
- Virology
- Drug Discovery
Background:
- Peramivir is an effective intravenous antiviral for influenza but shows reduced efficacy against the H275Y mutant.
- The H275Y mutation in influenza neuraminidase (NA) significantly impacts antiviral drug effectiveness.
- Developing novel influenza antivirals active against resistant strains is crucial.
Purpose of the Study:
- To synthesize and evaluate peramivir-caffeic acid conjugates for enhanced antiviral activity.
- To investigate the efficacy of these conjugates against both wild-type and H275Y influenza viruses.
- To explore the potential of these conjugates as orally available anti-influenza therapeutics.
Main Methods:
- Chemical synthesis of peramivir-caffeic acid conjugates (8 and 9).
- In vitro enzymatic assays to determine neuraminidase inhibitory activity (IC50).
- Cell-based assays for cytoprotective effects (EC50) against influenza virus infection.
- Molecular modeling to understand binding interactions with H275Y neuraminidase.
- In vivo efficacy studies in mice infected with influenza viruses.
Main Results:
- Conjugates 8 and 9 exhibited potent neuraminidase inhibition against wild-type and H275Y strains (nanomolar IC50).
- Molecular modeling indicated favorable interactions of conjugate 9 within the H275Y NA active site, compensating for resistance mutations.
- Conjugates demonstrated superior protection of MDCK cells from H275Y influenza infection compared to peramivir.
- Oral administration of conjugates 8 and 9 was effective in treating lethal influenza infections in mice.
Conclusions:
- Peramivir-caffeic acid conjugates are effective against both wild-type and H275Y influenza viruses.
- Conjugate 9, with its stable amide linkage, is a promising candidate for development as an orally administered anti-influenza drug active against resistant strains.
- The enhanced lipophilicity and binding interactions contribute to the improved efficacy of the conjugates.
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