权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Selective Stalling of Human Translation by Small Molecules

小分子对人类翻译的选择性停滞

基本信息

批准号：
10004692
负责人：
JAMIE H CATE
金额：
$ 29.59万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004692
关键词：
Amino Acid Sequence Amino Acid Substitution Amino Acids Back Behavior Binding Biochemical Biological Assay CRISPR interference Cells Clinic Complex Cryoelectron Microscopy DNA-Protein Interaction Data Development Disease Drug Targeting Effectiveness Escherichia coli Exhibits FRAP1 gene Family Foundations Future G protein coupled receptor kinase Genetic Human Libraries Maps Messenger RNA Modeling Molecular Mutation Nonsense Codon Nucleotides Pathway interactions Peptide Initiation Factors Pharmaceutical Preparations Play Protein Family Proteins Proteome Quality Control RNA, Ribosomal, 23S Reporter Resolution Ribosomal Proteins Ribosomal RNA Ribosomes Role Signal Pathway Structural Models Structure System Technology Testing Therapeutic Translation Initiation Translations Viral Proteins Virus base drug candidate guided inquiry human disease insight interest multicatalytic endopeptidase complex overexpression polypeptide prevent protein complex protein degradation reconstitution ribosome profiling small molecule therapeutic development transcription factor translation to humans

项目摘要

ABSTRACT Protein targets for many human diseases remain “undruggable” due to their underlying biochemical behavior. These limits to discovery of small molecule drugs hold back the promise of developing affordable therapeutics. Here we propose to develop an entirely new mechanism of action that could enable targeting previously “undruggable” proteins, by selectively blocking their translation by the human ribosome. Most drugs and drug candidates known to modulate human translation target translation initiation factor complexes or upstream signaling pathways such as mammalian target of Rapamycin (mTOR). These generally modulate translation of a large number of mRNAs. To date, only one type of compound that selectively targets the ribosome–to induce premature stop codon readthrough–is being evaluated in the clinic. We recently demonstrated that small molecules can selectively stall the translation of human proteins, with very little off-target activity. The compound we analyzed, PF-06446846 (PF846), directly and selectively inhibits the translation of PCSK9 during translation elongation, by stalling the ribosome on the nascent polypeptide residing in the ribosome exit tunnel. However, it remains unclear how this and related compounds selectively stall translation. The few examples of off-target proteins we identified as stalled by PF846 (less than 0.4 percent of the human proteome) exhibit substantial primary structure variability, making it difficult to predict target sequences for future development of selective ribosome-targeting drugs. We have preliminary evidence that PF846 interacts with these diverse nascent chain sequences to induce ribosome stalling by subtly different mechanisms. We propose to elucidate the full molecular mechanism of PF846 stalling of translation, so that this family of compounds can be further optimized to target proteins whose expression or overexpression causes diverse human diseases for which no treatments are now available. This family of compounds could also be optimized to target viruses, which use human translation to synthesize their proteome. These efforts have the potential to open up an entirely new mechanism of action for human therapeutic development.

摘要