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:
- 金额:$ 29.59万
- 依托单位:
- 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:
- 关键词:Amino Acid SequenceAmino Acid SubstitutionAmino AcidsBackBehaviorBindingBiochemicalBiological AssayCRISPR interferenceCellsClinicComplexCryoelectron MicroscopyDNA-Protein InteractionDataDevelopmentDiseaseDrug TargetingEffectivenessEscherichia coliExhibitsFRAP1 geneFamilyFoundationsFutureG protein coupled receptor kinaseGeneticHumanLibrariesMapsMessenger RNAModelingMolecularMutationNonsense CodonNucleotidesPathway interactionsPeptide Initiation FactorsPharmaceutical PreparationsPlayProtein FamilyProteinsProteomeQuality ControlRNA, Ribosomal, 23SReporterResolutionRibosomal ProteinsRibosomal RNARibosomesRoleSignal PathwayStructural ModelsStructureSystemTechnologyTestingTherapeuticTranslation InitiationTranslationsViral ProteinsVirusbasedrug candidateguided inquiryhuman diseaseinsightinterestmulticatalytic endopeptidase complexoverexpressionpolypeptidepreventprotein complexprotein degradationreconstitutionribosome profilingsmall moleculetherapeutic developmenttranscription factortranslation 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
项目成果
期刊论文数量(0)
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JAMIE H CATE其他文献
JAMIE H CATE的其他文献
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{{ truncateString('JAMIE H CATE', 18)}}的其他基金
Selective Stalling of Human Translation by Small Molecules
小分子对人类翻译的选择性停滞
- 批准号:
10443568 - 财政年份:2019
- 资助金额:
$ 29.59万 - 项目类别:
Selective Stalling of Human Translation by Small Molecules
小分子对人类翻译的选择性停滞
- 批准号:
10194545 - 财政年份:2019
- 资助金额:
$ 29.59万 - 项目类别:
STRUCTURES OF THE E COLI 70S RIBOSOME IN FUNCTIONAL COMPLEXES
功能复合物中大肠杆菌 70S 核糖体的结构
- 批准号:
7954332 - 财政年份:2009
- 资助金额:
$ 29.59万 - 项目类别:
STRUCTURES OF THE E COLI 70S RIBOSOME IN FUNCTIONAL COMPLEXES
功能复合物中大肠杆菌 70S 核糖体的结构
- 批准号:
7721984 - 财政年份:2008
- 资助金额:
$ 29.59万 - 项目类别:
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