2. Academic Validation
  3. Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction

Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction

  • Eur J Med Chem. 2017 Jan 5;125:1051-1063. doi: 10.1016/j.ejmech.2016.10.045.
Feng-Hua Zhang 1,  Bikash Debnath 2,  Zhong-Liang Xu 1,  Liu-Meng Yang 3,  Li-Rui Song 1,  Yong-Tang Zheng 3,  Nouri Neamati 4,  Ya-Qiu Long 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2800, USA.
  • 3 Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2800, USA. Electronic address: neamati@umich.edu.
  • 5 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: yqlong@simm.ac.cn.
PMID: 27810592 DOI: 10.1016/j.ejmech.2016.10.045
Abstract

Currently, three HIV-1 integrase (IN) active site-directed inhibitors are in clinical use for the treatment of HIV Infection. However, emergence of drug resistance mutations have limited the promise of a long-term cure. As an alternative, allosteric inhibition of IN activity has drawn great attention and several of such inhibitors are under early stage clinical development. Specifically, inhibitors of IN and the cellular cofactor LEDGF/p75 remarkably diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Distinct from the extensively studied 2-(quinolin-3-yl) acetic acid or 1H-indol-3-yl-2-hydroxy-4-oxobut-2-enoic acid chemotypes, this study discloses a new class of selective IN-LEDGF/p75 inhibitors without the carboxylic acid functionality. More significantly, 3-hydroxypicolinamides also show low micromolar inhibition against IN dimerization, providing novel dual IN inhibitors with in vitro therapeutically selective Antiviral effect for further development. Finally, our shape-based ROCS pharmacophore model of the 3-hydroxypicolinamide class of compounds provides a new insight into the binding mode of these novel IN-LEDGF/p75 inhibitors.

Keywords

3-Hydroxypicolinamide; Allosteric inhibitor; Dimerization; HIV-1 integrase; LEDGF/p75.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12109
    HIV-1 IN Chain Transfer Inhibitor
    HIV