Anti-HIV Effects of Baculiferins Are Regulated by the Potential Target Protein DARS.
ACS Chem Biol
; 16(8): 1377-1389, 2021 08 20.
Article
in En
| MEDLINE
| ID: mdl-34338505
ABSTRACT
Baculiferins are a group of marine sponge-derived polycyclic alkaloids with anti-HIV (human immunodeficiency virus) activities. To identify additional baculiferin-based congeners for SAR analysis and to investigate the mode of action, a total of 18 new baculiferin-type derivatives were synthesized. The inhibitory activities of the congeners against the HIV-1 virus were evaluated in vitro, and the relevant SAR was discussed. Compound 18 exerted the most potent activity toward VSV-G-pseudotyped HIV-1 (IC50 of 3.44 µM) and HIV-1 strain SF33 (IC50 of 2.80 µM) in vitro. To identify the cellular targets, three photoaffinity baculiferin probes were simultaneously synthesized. Photoaffinity labeling experiments together with LC-MS/MS data identified aspartate-tRNA ligase (DARS) as a putative target protein of 18. The overexpression and knockdown of DARS in HEK293T cells provided additional data to demonstrate that DARS is a potential target protein in the regulation of HIV virus infection. The modes of antiviral baculiferins 13 and 18 binding to DARS were determined by a molecular docking simulation. Thus, baculiferin 18 is considered a promising lead as a new molecular target for the development of anti-HIV agents.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Aspartate-tRNA Ligase
/
HIV-1
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Anti-HIV Agents
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Alkaloids
/
Enzyme Inhibitors
Limits:
Humans
Language:
En
Journal:
ACS Chem Biol
Year:
2021
Document type:
Article