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CAS - Science Connections
Single Amino Acid Substitutions Spell Trouble for the Latest Antiviral Drugs
Feeling achy, feverish, fatigued... do you have the flu? According to recent data from the Centers for Disease Control and Prevention (CDC), there's a good chance you've been infected by an influenza A virus.1 Unfortunately, each flu season brings new strains of the influenza A virus, some of which have become highly resistant to existing antiviral drugs. Since the 1999-2000 flu season, your physician could have prescribed one of four licensed influenza antiviral drugs to help shorten the duration of your illness or to prevent infection entirely:
While these antiviral drugs have been used successfully in combination with annual flu vaccinations to combat influenza infections, experience in recent years has shown the influenza A virus to be a moving target. On February 22, 2006, the Journal of the American Medical Association published a report from the CDC indicating that influenza A viruses of the H3N2 subtype had become highly resistant to M2 inhibitors.2 A single amino acid substitution in the viral M2 protein rendered the inhibitors useless against infection, and as a result, neuraminidase inhibitors became the only antiviral drugs recommended for the prevention and treatment of influenza A (H3N2) infections.1 Three years later, preliminary data for the 2008-2009 flu season indicate that influenza A viruses of the H1N1 subtype have become resistant to the neuraminidase inhibitor Tamiflu (oseltamivir). According to a recent report in the Journal of the American Medical Association, "As of February 19, 2009, resistance to oseltamivir had been identified among 264 of 268 US influenza A (H1N1) viruses (98.5%) tested."3 Similar to M2 inhibitor resistance, Tamiflu resistance appears to be due to a single amino acid substitution.3 In this case, histidine (CAS Registry Number 71-00-1) is replaced with tyrosine (CAS Registry Number 60-18-4) at position 274 in the catalytic site of the viral neuraminidase enzyme. Newly replicated viruses rely on neuraminidase enzyme activity to break free from the host cell, facilitating the spread of infection. Tamiflu inhibits the spread by blocking the enzyme's catalytic site from its natural substrate, sialic acid (CAS Registry Number 131-48-6).4 Resistance to Tamiflu developed in influenza A (H1N1) viruses because the presence of tyrosine effectively prevents the drug, but not sialic acid, from binding to the catalytic site of the neuraminidase enzyme. With nearly all of the influenza A (H1N1) viruses circulating in the U.S. reported to be resistant to Tamiflu - the result of a single amino acid substitution - the CDC was compelled to issue a Health Advisory with interim recommendations for the use of antiviral drugs:
You can use SciFinder or STN to search the CAS databases for additional information about influenza viruses and antiviral drugs. If your organization is enabled to use the web version of SciFinder, you can click the links in this article to directly access details of the substances and references. Contributed by
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