TY - JOUR
T1 - A Novel Method of Resistance for Influenza Against a Channel-Blocking Antiviral Drug
AU - Astrahan, Peleg
AU - Kass, Itamar
AU - Cooper, Matthew A.
AU - Arkin, Isaiah T.
PY - 2004/5/1
Y1 - 2004/5/1
N2 - Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H+ channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease.
AB - Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H+ channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease.
KW - Antiviral
KW - Channel blocker
KW - Influenza
KW - Ion channel
KW - Protein structure
UR - http://www.scopus.com/inward/record.url?scp=1842427673&partnerID=8YFLogxK
U2 - 10.1002/prot.20018
DO - 10.1002/prot.20018
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C2 - 15048819
AN - SCOPUS:1842427673
SN - 0887-3585
VL - 55
SP - 251
EP - 257
JO - Proteins: Structure, Function and Genetics
JF - Proteins: Structure, Function and Genetics
IS - 2
ER -