@article { WOS:000364124100005, title = {Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead}, journal = {INTERNATIONAL JOURNAL OF PHARMACEUTICS}, volume = {495}, year = {2015}, note = {[[{"fid":"263826","view_mode":"default","type":"media","attributes":{"style":"width: 450px; height: 219px;","alt":"s2","class":"img-responsive media-element file-default "}}]] }, month = {NOV 30}, pages = {660-663}, abstract = {

Chirality is an important aspect in many pharmacological processes including drug transport and metabolism. The current investigation examined the stereospecific transport and entry inhibitory activity of four diastereomers derived from a small (macrocyclic) molecule that has two chiral centers. These molecules were designed to mimic the interaction between CD4 and gp120 site of HIV-1 and thereby to function as entry inhibitor(s). Intestinal permeability was assessed by ex-vivo model using excised rat intestine mounted in side-byside diffusion chambers. The entry inhibitory activity was monitored using indicator HeLa-CD4-LTR-beta-gal cells (MAGI assay). The (S/S) diastereomer, named CG-1, exhibited superiority in both unrelated tested biological processes: (I) high transport through the intestine and (II) entry inhibition activity (in the low mu M range). The permeability screening revealed a unique transporter-mediated absorption pathway of CG-1, suggesting a significant role of the molecule{\textquoteright}s conformation on the mechanism of intestinal absorption. Here we highlight that only the S, S enantiomer (CG-1) has both (I) promising anti HIV-1 entry inhibitory properties and (II) high transporter mediated intestinal permeability. Hence we suggest preference in pharmacological processes to the S, S conformation. This report augments the knowledge regarding stereoselectivity in receptor mediated and protein-protein interaction processes. (C) 2015 Elsevier B.V. All rights reserved.

}, issn = {0378-5173}, doi = {10.1016/j.ijpharm.2015.09.027}, author = {Fanous, Joseph and Swed, Avi and Joubran, Salim and Mattan Hurevich and Britan-Rosich, Elena and Kotler, Moshe and Gilon, Chaim and Amnon Hoffman} }