Detailed Mechanistic Insights into HIV-1 Sensitivity to Three Generations of Fusion Inhibitors
Detailed Mechanistic Insights into HIV-1 Sensitivity to Three Generations of Fusion Inhibitors
复制标题
DOI：
10.1074/jbc.m109.004416
复制
发表时间：
2009-09-25
影响因子：
4.8
通讯作者：
Sanders, Rogier W.
中科院分区：
文献类型：
--
作者：
Eggink, Dirk;Langedijk, Johannes P. M.;Sanders, Rogier W.
基于病毒I类融合蛋白的第二个七肽重复序列（HR 2）的肽是病毒进入的有效抑制剂。一种这样的融合抑制剂已被批准用于治疗人免疫缺陷病毒-1（T20，恩夫韦肽）。对T20的抗性通常映射到HR 1中的肽结合位点。为了更好地理解融合抑制剂的效力和抗性，我们将病毒学、计算和生物物理学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）的抗性。我们发现大多数氨基酸替换引起对第一代肽T20的抗性。只有带电荷的氨基酸引起对T1249的抗性，而没有引起对T2635的抗性。根据药物的不同，我们可以区分出四种耐药机制：接触减少、空间阻碍、静电排斥和静电吸引。新型抗病毒肽抑制剂的设计的影响进行了讨论。
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.