Discovery of novel 3-hydroxypicolinamides as selective inhibitors of HIV-1 integrase-LEDGF/p75 interaction.
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.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Feng-Hua
FH
Zhang
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2800, USA.
Bikash
B
Debnath
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Zhong-Liang
ZL
Xu
Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Liu-Meng
LM
Yang
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Li-Rui
LR
Song
Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Yong-Tang
YT
Zheng
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2800, USA. Electronic address: neamati@umich.edu.
Nouri
N
Neamati
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.
Ya-Qiu
YQ
Long
D000494:Allosteric Regulation / Q000187:drug effects; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D062105:Molecular Docking Simulation; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010848:Picolinic Acids; C119380:lens epithelium-derived growth factor; C070035:3-hydroxypicolinamide; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
3-Hydroxypicolinamide; Allosteric inhibitor; Dimerization; HIV-1 integrase; LEDGF/p75