HIV-1 integrase (IN) is composed of three domains, the N-termi-
nal domain (NTD, residues 1–50), the catalytic core domain (CCD,
residues 51–212), and the C-terminal domain (CTD, residues 213–
288). All the three domains are required for the two known inte-
gration reactions. CCD contains the catalytic triad and is believed
to bind viral DNA specifically, and CTD binds viral DNA in a non-
specific manner. As no clear evidence has confirmed the involve-
ment of NTD in DNA binding directly, NTD has not been seriously
considered and less is known about its function in viral replica-
tion. In the current work, using a SPR technology-based assay,
the HIV-1 viral DNA was determined to bind directlyto NTD with
a KD value of 8.8 mm, suggesting that the process of preintegrat-
ed complex formation for HIV-1 IN might involve the direct inter-
action of NTD with viral DNA in addition to binding of viral DNA

to the catalytic core domain and C-terminal domain. Moreover,
such viral DNA/IN binding could be inhibited bythe marine product
hyrtiosal from the marine sponge Hyrtios erectus with an
IC50 of 9.600.86 mm. Molecular dynamic analysis correlated
with a site-directed mutagenesis approach further revealed that
such hyrtiosal-induced viral DNA/IN binding inhibition was
caused bythe fact that hyrtiosal could bind HIV-1 NTD at Ser17,
Trp19, and Lys34. As hyrtiosal was recently discovered by us as a
protein tyrosine phosphatase 1B (PTP1B) inhibitor,[1] this work
might also supplymultipl e-target information for this marine
product, and the verified HIV-NTD/HIV-1 IN interaction model
could have further implications for new HIV-1 IN inhibitor design
and evaluation.