1,2,3,4-Tetrahydroisoquinolines as inhibitors of HIV-1 integrase and human LEDGF/p75 interaction.
Chem Biol Drug Des
; 91(6): 1133-1140, 2018 06.
Article
in En
| MEDLINE
| ID: mdl-29405651
ABSTRACT
Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75-IN interaction in vitro with an IC50 of ~10 µm. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75-binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non-specific DNA. As reported earlier for the inhibitors of LEDGF/p75-IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV-1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75-IN interaction having a higher potency.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
HIV Integrase Inhibitors
/
HIV Integrase
/
Tetrahydroisoquinolines
/
Adaptor Proteins, Signal Transducing
Limits:
Humans
Language:
En
Journal:
Chem Biol Drug Des
Journal subject:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Year:
2018
Document type:
Article
Affiliation country:
India
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM