Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead

Joseph Fanous, Avi Swed, Salim Joubran, Mattan Hurevich, Elena Britan-Rosich, Moshe Kotler, Chaim Gilon, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageAmerican English
Pages (from-to)660-663
Number of pages4
JournalInternational Journal of Pharmaceutics
Volume495
Issue number2
DOIs
StatePublished - 30 Nov 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.

Keywords

  • AIDS
  • Intestinal transporter
  • Pharmacodynamics
  • Pharmacokinetics
  • Stereoselectivity

Fingerprint

Dive into the research topics of 'Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead'. Together they form a unique fingerprint.

Cite this