Development of 7SK snRNA Mimics That Inhibit HIV Transcription

Asako Yamayoshi; Hiroyuki Fukumoto; Rie Hayashi; Kyosuke Kishimoto; Akio Kobori; Yoshio Koyanagi; Jun A Komano; Akira Murakami

doi:10.1002/cmdc.202100422

Development of 7SK snRNA Mimics That Inhibit HIV Transcription

ChemMedChem. 2021 Oct 15;16(20):3181-3184. doi: 10.1002/cmdc.202100422. Epub 2021 Jul 26.

Authors

Asako Yamayoshi¹, Hiroyuki Fukumoto², Rie Hayashi², Kyosuke Kishimoto², Akio Kobori², Yoshio Koyanagi³, Jun A Komano⁴, Akira Murakami²

Affiliations

¹ Chemistry of Functional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi Nagasaki-shi, Nagasaki, 852-8521, Japan.
² Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki Sakyo-ku, Kyoto, 606-8585, Japan.
³ Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-kawaramachi 53 Sakyo-ku, Kyoto, 606-8507, Japan.
⁴ Department of Microbiology and Infection Control, Faculty and Graduate School of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1041, Japan.

PMID: 34233081
DOI: 10.1002/cmdc.202100422

Abstract

The 332-nucleotide small nuclear RNA (snRNA) 7SK is a highly conserved non-coding RNA that regulates transcriptional elongation. By binding with positive transcriptional elongation factor b (P-TEFb) via HEXIM1, 7SK snRNA decreases the kinase activity of P-TEFb and inhibits transcriptional elongation. Additionally, it is reported that 7SK inhibition results in the stimulation of human immunodeficiency virus (HIV)-specific transcription. These reports suggest that 7SK is a naturally occurring functional molecule as negative regulator of P-TEFb and HIV transcription. In this study, we developed functional oligonucleotides that mimic the function of 7SK (7SK mimics) as novel inhibitors of HIV replication. We defined the essential region of 7SK regarding its suppressive effects on transcriptional downregulation using an antisense strategy. Based on the results, we designed 7SK mimics containing the defined region. The inhibitory effects of 7SK mimics on HIV-1 long terminal repeat promoter specific transcription was drastic compared with those of the control mimic molecule. Notably, these effects were found to be more enhanced by co-transfection with Tat-expressing plasmids. From these results, it is indicated that 7SK mimics may have great therapeutic potential for HIV/AIDS treatment.

Keywords: 7SK; HIV; non-coding RNA; nucleic acid drug; transcriptional inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Development*
Molecular Structure
RNA, Small Nuclear / chemical synthesis
RNA, Small Nuclear / chemistry
RNA, Small Nuclear / pharmacology*
Structure-Activity Relationship
Transcription, Genetic / drug effects*
Transcription, Genetic / genetics
tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
tat Gene Products, Human Immunodeficiency Virus / genetics

Substances

RNA, Small Nuclear
tat Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding