TY - JOUR
T1 - Characterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino-terminal heptad repeat
AU - Izumi, Kazuki
AU - Nakamura, Shota
AU - Nakano, Hiroaki
AU - Shimura, Kazuya
AU - Sakagami, Yasuko
AU - Oishi, Shinya
AU - Uchiyama, Susumu
AU - Ohkubo, Tadayasu
AU - Kobayashi, Yuji
AU - Fujii, Nobutaka
AU - Matsuoka, Masao
AU - Kodama, Eiichi N.
N1 - Funding Information:
This work was supported in part by a grant for the Promotion of AIDS Research from the Ministry of Health and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (E.K. and S.O.); and a grant for Research for Health Sciences Focusing on Drug Innovation from The Japan Health Sciences Foundation (E.K., S.O., N.F. and M.M.).
PY - 2010/8
Y1 - 2010/8
N2 - A transmembrane glycoprotein of HIV-1, gp41, plays a central role in membrane fusion of HIV-1 and host cells. Peptides derived from the amino- and carboxyl-terminal heptad repeat (N-HR and C-HR, respectively) of gp41 inhibit this fusion. The mechanism of resistance to enfuvirtide, a C-HR-derived peptide, is well defined; however the mechanism of resistance to N-HR-derived peptides remains unclear. We characterized an HIV-1 isolate resistant to the N-HR-derived peptide, N36. This HIV-1 acquired a total of four amino acid substitutions, D36G, N126K and E137Q in gp41, and P183Q in gp120. Among these substitutions, N126K and/or E137Q conferred resistance to not only N36, but also C34, which is the corresponding C-HR-derived peptide fusion inhibitor. We performed crystallographic and biochemical analysis of the 6-helix bundle formed by synthetic gp41-derived peptides containing the N126K/E137Q substitutions. The structure of the 6-helix bundle with N126K/E137Q was identical to that in wild-type HIV-1 except for the presence of a new hydrogen bond. Denaturing experiments revealed that the stability of the 6-helix bundle of N126K/E137Q is greater than in the wild-type. These results suggest that the stabilizing effect of N126K/E137Q provides resistance to N36 and C34.
AB - A transmembrane glycoprotein of HIV-1, gp41, plays a central role in membrane fusion of HIV-1 and host cells. Peptides derived from the amino- and carboxyl-terminal heptad repeat (N-HR and C-HR, respectively) of gp41 inhibit this fusion. The mechanism of resistance to enfuvirtide, a C-HR-derived peptide, is well defined; however the mechanism of resistance to N-HR-derived peptides remains unclear. We characterized an HIV-1 isolate resistant to the N-HR-derived peptide, N36. This HIV-1 acquired a total of four amino acid substitutions, D36G, N126K and E137Q in gp41, and P183Q in gp120. Among these substitutions, N126K and/or E137Q conferred resistance to not only N36, but also C34, which is the corresponding C-HR-derived peptide fusion inhibitor. We performed crystallographic and biochemical analysis of the 6-helix bundle formed by synthetic gp41-derived peptides containing the N126K/E137Q substitutions. The structure of the 6-helix bundle with N126K/E137Q was identical to that in wild-type HIV-1 except for the presence of a new hydrogen bond. Denaturing experiments revealed that the stability of the 6-helix bundle of N126K/E137Q is greater than in the wild-type. These results suggest that the stabilizing effect of N126K/E137Q provides resistance to N36 and C34.
KW - Amino-terminus
KW - Fusion
KW - Gp41
KW - HIV-1
KW - Resistance
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U2 - 10.1016/j.antiviral.2010.04.011
DO - 10.1016/j.antiviral.2010.04.011
M3 - Article
C2 - 20438763
AN - SCOPUS:77954956891
SN - 0166-3542
VL - 87
SP - 179
EP - 186
JO - Antiviral Research
JF - Antiviral Research
IS - 2
ER -
