Eggink Dirk, Langedijk Johannes P M, Bonvin Alexandre M J J, Deng Yiqun, Lu Min, Berkhout Ben, Sanders Rogier W
Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
J Biol Chem. 2009 Sep 25;284(39):26941-50. doi: 10.1074/jbc.M109.004416. Epub 2009 Jul 17.
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.
基于病毒I类融合蛋白第二个七肽重复序列（HR2）的肽是有效的病毒进入抑制剂。一种这样的融合抑制剂已被批准用于治疗人类免疫缺陷病毒1型（T20，恩夫韦肽）。对T20的耐药性通常定位在HR1中的肽结合位点。为了更好地理解融合抑制剂的效力和耐药性，我们将病毒学、计算和生物物理实验与全面的突变分析相结合，并测试了对T20以及第二代和第三代抑制剂（T1249和T2635）的耐药性。我们发现，大多数氨基酸替代导致对第一代肽T20产生耐药性。只有带电荷的氨基酸导致对T1249产生耐药性，而没有氨基酸导致对T2635产生耐药性。根据药物的不同，我们可以区分四种耐药机制：接触减少、空间位阻、静电排斥和静电吸引。文中讨论了对新型抗病毒肽抑制剂设计的启示。
