Santhosh K C, Paul G C, De Clercq E, Pannecouque C, Witvrouw M, Loftus T L, Turpin J A, Buckheit R W, Cushman M
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2001 Mar 1;44(5):703-14. doi: 10.1021/jm000290u.
Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.
考沙兰及其合成衍生物可抑制gp120与CD4的结合以及病毒包膜与细胞膜的融合。据推测，考沙兰与CD4的结合涉及配体带负电荷的羧酸盐与蛋白质带正电荷的精氨酸和赖氨酸氨基酸侧链之间的离子相互作用。为了研究阴离子间距对考沙兰系统抗HIV活性的影响，合成了一系列考沙兰四羧酸盐，其中两个近端羧酸盐和两个远端羧酸盐被6至12个原子隔开。当近端和远端羧酸盐被8个原子隔开时，观察到最大活性。在一系列含有谷氨酸、甘氨酸、天冬氨酸、β-丙氨酸、亮氨酸和苯丙氨酸残基的考沙兰氨基酸衍生物中，二（谷氨酸）类似物表现出最大活性。已经设计了一个考沙兰二（谷氨酸）缀合物与CD4结合的假设模型。一般来说，该系列化合物在CEM-SS细胞中对HIV-1（RF）的活性比对MT-4细胞中的HIV-1（IIIB）更强，而在MT-4细胞中对HIV-2（ROD）的活性最弱。
