title: Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead.
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-by-side 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 μM range). The permeability screening revealed a unique transporter-mediated absorption pathway of CG-1, suggesting a significant role of the molecule'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.
authors.affiliation: Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fanous
authors.affiliation: Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Swed
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Salim
authors.initials: S
authors.lastname: Joubran
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Mattan
authors.initials: M
authors.lastname: Hurevich
authors.affiliation: Department of Pathology and the Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Britan-Rosich
authors.affiliation: Department of Pathology and the Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Kotler
authors.affiliation: Institute of Chemistry, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Chaim
authors.initials: C
authors.lastname: Gilon
authors.affiliation: Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel. Electronic address: amnonh@ekmd.huji.ac.il.
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; D001616:beta-Galactosidase
keywords: AIDS; Intestinal transporter; Pharmacodynamics; Pharmacokinetics; Stereoselectivity