Resistance to FDA Licensed Anti-Neuraminidase Drugs Used for Flu Treatment in the Americas: An Overview of the Incidence of Resistant-Strains of Seasonal and Pandemic Influenza Viruses from 2004 to 2014
Pp. 3-30 (28)
L.A.M.G. Fornells and J.N.S.S. Couceiro
Influenza A and B viruses are RNA viruses that present neuraminidase as
one of their envelope-inserted glycoproteins. These viruses, because of their complexity
and high mutation rates, exhibit high prevalence among human beings and are causal
agents of annual flu epidemics. They are responsible for significant morbidity and
mortality and cause 250,000 to 500,000 deaths worldwide per year, especially among
the elderly, children and patients presenting respiratory, renal and cardiac diseases.
Through the centuries, influenza A viruses have been identified as agents of flu
pandemics. During infection, the viral neuraminidase plays a critical role in the virus
particles dissemination by releasing the terminal sialic acid residues on the
cytoplasmatic membrane by cleaving α-2,3 and α-2,6 ketosidic linkages, which involves
a chair-boat conformational change. Neuraminidase presents exo-glycohydrolase
activity, exhibiting an active site that is highly conserved in nine of the antigenic
neuraminidase subtypes of influenza A viruses. The neuramidase active site exhibits a
central rigid catalytic structure with 19 highly conserved amino acid residues and is thus
considered to be an interesting attractive target for the design of anti-influenza drugs.
Zanamivir and oseltamivir, two anti-influenza neuraminidase drugs, were introduced in
1999. However, since the anti-neuraminidase drugs were introduced, the appearance of
conformational changes responsible for the development of clinically relevant
resistance has become a critical topic. Resistance of influenza A H1N1 viruses to
oseltamivir was first observed in 2001, and the circulation of oseltamivir-resistant and
zanamivir-resistant samples of influenza A (H1N1 and H3N2) and B viruses have
already been observed. The most commonly reported cases of recent oseltamivirresistant
viruses present a 275 mutation (H275Y) on the neuraminidase (NA) molecule,
a substitution that is known to be responsible for high levels of resistance only to
oseltamivir; other point mutations have been observed to confer resistance to zanamivir
and peramivir. The aim of this chapter is to report the presence of mutations that induce
resistance to anti-neuraminidase drugs that have been licensed by the FDA for flu
treatment in the ten last years in the Americas.
Americas, influenza virus, laninamivir, oseltamivir, peramivir,
Department of Virology - Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, CCS - Bl. I - Campus, Fundão Island, Rio de Janeiro - RJ, 21941-902, Brazil.