| RRC ID |
63487
|
| 著者 |
Kamo M, Ito M, Toma T, Gotoh H, Shimozono R, Nakagawa R, Koga R, Monde K, Tateishi H, Misumi S, Otsuka M, Fujita M.
|
| タイトル |
Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.
|
| ジャーナル |
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.
|
| 巻・号 |
107
|
| ページ |
104627
|
| 公開日 |
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
|
| リソース情報 |
| 遺伝子材料 |
Genome Network Project Human cDNA Clone IRAK029O09 (HGX011945) |
| ヒト・動物細胞 |
A549(RCB0098) |
