TY - JOUR
T1 - Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors
AU - Eggink, Dirk
AU - Langedijk, Johannes P. M.
AU - Bonvin, Alexandre M. J. J.
AU - Deng, Yiqun
AU - Lu, Min
AU - Berkhout, Ben
AU - Sanders, Rogier W.
PY - 2009
Y1 - 2009
N2 - Peptides based on the second heptad repeat (HR2) of viral class I fusion proteins are effective inhibitors of virus entry. One such fusion inhibitor has been approved for treatment of human immunodeficiency virus-1 (T20, enfuvirtide). Resistance to T20 usually maps to the peptide binding site in HR1. To better understand fusion inhibitor potency and resistance, we combined virological, computational, and biophysical experiments with comprehensive mutational analyses and tested resistance to T20 and second and third generation inhibitors (T1249 and T2635). We found that most amino acid substitutions caused resistance to the first generation peptide T20. Only charged amino acids caused resistance to T1249, and none caused resistance to T2635. Depending on the drug, we can distinguish four mechanisms of drug resistance: reduced contact, steric obstruction, electrostatic repulsion, and electrostatic attraction. Implications for the design of novel antiviral peptide inhibitors are discussed
AB - Peptides based on the second heptad repeat (HR2) of viral class I fusion proteins are effective inhibitors of virus entry. One such fusion inhibitor has been approved for treatment of human immunodeficiency virus-1 (T20, enfuvirtide). Resistance to T20 usually maps to the peptide binding site in HR1. To better understand fusion inhibitor potency and resistance, we combined virological, computational, and biophysical experiments with comprehensive mutational analyses and tested resistance to T20 and second and third generation inhibitors (T1249 and T2635). We found that most amino acid substitutions caused resistance to the first generation peptide T20. Only charged amino acids caused resistance to T1249, and none caused resistance to T2635. Depending on the drug, we can distinguish four mechanisms of drug resistance: reduced contact, steric obstruction, electrostatic repulsion, and electrostatic attraction. Implications for the design of novel antiviral peptide inhibitors are discussed
U2 - https://doi.org/10.1074/jbc.M109.004416
DO - https://doi.org/10.1074/jbc.M109.004416
M3 - Article
C2 - 19617355
SN - 0021-9258
VL - 284
SP - 26941
EP - 26950
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 39
ER -