Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.

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.

• Authors: Masahiro Kamo, Miu Ito, Tsugumasa Toma, Haruna Gotoh, Rie Shimozono, Riko Nakagawa, Ryoko Koga, Kazuaki Monde, Hiroshi Tateishi, Shogo Misumi, Masami Otsuka, Mikako Fujita
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 107 Pg. 104627 (02 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33476868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Anti-HIV Agents
• Heterocyclic Compounds
• Heterogeneous-Nuclear Ribonucleoprotein Group M
• Hyaluronan Receptors
• Pyrimidines
• RNA, Small Interfering

Topics

• Anti-HIV Agents (chemistry, metabolism, pharmacology)
• Cell Line
• Cell Movement (drug effects)
• Down-Regulation (drug effects)
• Drug Evaluation, Preclinical
• Heterocyclic Compounds (chemistry, metabolism, pharmacology)
• Heterogeneous-Nuclear Ribonucleoprotein Group M (antagonists & inhibitors, genetics, metabolism)
• Humans
• Hyaluronan Receptors (genetics, metabolism)
• Protein Binding
• Pyrimidines (chemistry, metabolism, pharmacology)
• RNA Interference
• RNA, Small Interfering (chemistry, metabolism)