RRC ID 63487
Author Kamo M, Ito M, Toma T, Gotoh H, Shimozono R, Nakagawa R, Koga R, Monde K, Tateishi H, Misumi S, Otsuka M, Fujita M.
Title Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.
Journal Bioorg Chem
Abstract One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-β (TGF-β). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.
Volume 107
Pages 104627
Published 2021-2-1
DOI 10.1016/j.bioorg.2021.104627
PII S0045-2068(21)00003-1
PMID 33476868
MeSH Anti-HIV Agents / chemistry* Anti-HIV Agents / metabolism Anti-HIV Agents / pharmacology Cell Line Cell Movement / drug effects Down-Regulation / drug effects Drug Evaluation, Preclinical Heterocyclic Compounds / chemistry* Heterocyclic Compounds / metabolism Heterocyclic Compounds / pharmacology Heterogeneous-Nuclear Ribonucleoprotein Group M / antagonists & inhibitors Heterogeneous-Nuclear Ribonucleoprotein Group M / genetics Heterogeneous-Nuclear Ribonucleoprotein Group M / metabolism* Humans Hyaluronan Receptors / genetics Hyaluronan Receptors / metabolism Protein Binding Pyrimidines / chemistry Pyrimidines / metabolism Pyrimidines / pharmacology RNA Interference RNA, Small Interfering / chemistry RNA, Small Interfering / metabolism
IF 4.831
DNA material Genome Network Project Human cDNA Clone IRAK029O09 (HGX011945)
Human and Animal Cells A549(RCB0098)