Anti-HIV Effects of Baculiferins Are Regulated by the Potential Target Protein DARS

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.