Peramivir conjugates as orally available agents against influenza H275Y mutant

Peramivir conjugates as orally available agents against influenza H275Y mutant 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Peramivir conjugates as orally available agents against influenza H275Y mutant

European Journal of Medicinal Chemistry 145 (2018) 224e234 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Research paper Peramivir conjugates as orally available agents against influenza H275Y mutant a, 1 a, 1 b b b Peng-Cheng Wang , Din-Chi Chiu , Jia-Tsrong Jan , Wen-I Huang , Yin-Chen Tseng , b b c, d a, b, * Ting-Ting Li , Ting-Jen Cheng , Keng-Chang Tsai , Jim-Min Fang Department of Chemistry, National Taiwan University, Taipei 106, Taiwan The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan article i nf o abstract Article history: Peramivir is an efficacious neuraminidase (NA) inhibitor for treatment of influenza by intravenous Received 18 October 2017 administration. However, the efficacy of peramivir toward the H275Y mutant is appreciably reduced. To Received in revised form address this drawback, conjugation of peramivir with caffeic acid is devised in this study to enhance the 15 December 2017 binding affinity with neuraminidases. The C2-OH group of peramivir is elaborated to link with caffeate Accepted 20 December 2017 derivatives, giving the desired conjugates 8 and 9 that possess potent NA inhibitory activity against both Available online 24 December 2017 wild-type and H275Y viruses with the IC 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 Keywords: providing additional hydrogen bonds and hydrophobic interactions to compensate the reduced binding Peramivir affinity of the peramivir moiety due to Glu-276 dislocation in H275Y mutant. In comparison with per- Caffeic acid amivir, the lipophilicity of...
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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.12.072
Publisher site
See Article on Publisher Site

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.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Feb 10, 2018

References

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