Ghosh Arun K, Rao Kalapala Venkateswara, Nyalapatla Prasanth R, Osswald Heather L, Martyr Cuthbert D, Aoki Manabu, Hayashi Hironori, Agniswamy Johnson, Wang Yuan-Fang, Bulut Haydar, Das Debananda, Weber Irene T, Mitsuya Hiroaki
Department of Chemistry and Department of Medicinal Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.
J Med Chem. 2017 May 25;60(10):4267-4278. doi: 10.1021/acs.jmedchem.7b00172. Epub 2017 Apr 18.
Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
报道了一类新型高效HIV-1蛋白酶抑制剂的设计、合成及评估。抑制剂5展现出卓越的抗病毒活性和耐药性特征。事实上，该抑制剂相较于FDA批准的药物达芦那韦，抗病毒活性提高了几个数量级。此抑制剂包含一个前所未有的6-5-5环稠合冠状四氢吡喃并呋喃作为P2配体，以及一个氨基苯并噻唑作为P2'配体，并带有（R）-羟乙基磺酰胺电子等排体。使用手性狄尔斯-阿尔德催化剂以光学活性形式高效合成了该抑制剂的冠状P2配体，得到了高对映体纯度的关键中间体。与抑制剂结合的HIV-1蛋白酶的两个高分辨率X射线结构揭示了与HIV-1蛋白酶主链原子的广泛相互作用，并为这些新型抑制剂的结合特性提供了分子层面的见解。
