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J Virol. 2016 Sep 21. pii: JVI.01703-16. [Epub ahead of print]
Resistance to mutant group-2 influenza neuraminidases of an oseltamivir-zanamivir hybrid inhibitor.
Wu Y1, Gao F2, Qi J3, Bi Y1, Fu L3, Mohan S4, Chen Y2, Li X3, Pinto BM4, Vavricka CJ3, Tien P5, Gao GF6.
Author information
Abstract
Influenza neuraminidase (NA) drug-resistance is one of the challenges to preparedness against epidemic and pandemic influenza infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug-resistance of the influenza N1 NA is well characterized. Yet, drug-resistance of the N2 strain is not well understood. Here, we confirm that substitution of N2 E119 or I222 results in multi-drug resistance, and when occurring together the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we show that E119 substitution results in a loss of hydrogen bonding to oseltamivir and zanamivir whereas I222 substitution results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we find that MS-257, a zanamivir/oseltamivir hybrid inhibitor, is less susceptible to drug-resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug-resistant .MS-257 serves as a next-generation anti-influenza drug candidate and serves also as a scaffold for further design of NAIs.
IMPORTANCE:
Oseltamivir and zanamivir are the two major antiviral drugs available for the treatment of influenza virus infections. However, multi-drug resistant viruses have emerged in clinical cases, which pose a challenge for the development of new drugs. N1 and N2 subtypes exist in the viruses which cause seasonal epidemics and past pandemics. Although N1 drug resistance is well characterized, the molecular mechanisms underlying N2 drug resistance are unknown. A previous report showed that an N2 E119V/I222L dual mutant conferred drug resistance to seasonal influenza virus. Here, we confirm that these substitutions result in multi-drug resistance and dramatically reduced sensitivity to NAI. We further elucidate the molecular mechanism underlying N2 drug resistance by solving crystal structures of N2 E119V, I222L, and the dual mutant. Most importantly, we found that a novel oseltamivir/zanamivir hybrid inhibitor, MS-257, remains more effective against drug-resistant N2 and is a promising candidate as a next generation anti-influenza drug.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27654293 DOI: 10.1128/JVI.01703-16
[PubMed - as supplied by publisher]
Resistance to mutant group-2 influenza neuraminidases of an oseltamivir-zanamivir hybrid inhibitor.
Wu Y1, Gao F2, Qi J3, Bi Y1, Fu L3, Mohan S4, Chen Y2, Li X3, Pinto BM4, Vavricka CJ3, Tien P5, Gao GF6.
Author information
Abstract
Influenza neuraminidase (NA) drug-resistance is one of the challenges to preparedness against epidemic and pandemic influenza infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug-resistance of the influenza N1 NA is well characterized. Yet, drug-resistance of the N2 strain is not well understood. Here, we confirm that substitution of N2 E119 or I222 results in multi-drug resistance, and when occurring together the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we show that E119 substitution results in a loss of hydrogen bonding to oseltamivir and zanamivir whereas I222 substitution results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we find that MS-257, a zanamivir/oseltamivir hybrid inhibitor, is less susceptible to drug-resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug-resistant .MS-257 serves as a next-generation anti-influenza drug candidate and serves also as a scaffold for further design of NAIs.
IMPORTANCE:
Oseltamivir and zanamivir are the two major antiviral drugs available for the treatment of influenza virus infections. However, multi-drug resistant viruses have emerged in clinical cases, which pose a challenge for the development of new drugs. N1 and N2 subtypes exist in the viruses which cause seasonal epidemics and past pandemics. Although N1 drug resistance is well characterized, the molecular mechanisms underlying N2 drug resistance are unknown. A previous report showed that an N2 E119V/I222L dual mutant conferred drug resistance to seasonal influenza virus. Here, we confirm that these substitutions result in multi-drug resistance and dramatically reduced sensitivity to NAI. We further elucidate the molecular mechanism underlying N2 drug resistance by solving crystal structures of N2 E119V, I222L, and the dual mutant. Most importantly, we found that a novel oseltamivir/zanamivir hybrid inhibitor, MS-257, remains more effective against drug-resistant N2 and is a promising candidate as a next generation anti-influenza drug.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27654293 DOI: 10.1128/JVI.01703-16
[PubMed - as supplied by publisher]