Abstract:
:Receptors, enzymes, and ion channels are traditional targets of therapeutic development. A common strategy is to target these proteins with agents that either activate or suppress their activity with ligands or substrates that occupy orthosteric sites or have allosteric interactions. An alternative approach involves regulation of protein trafficking. In principle, this approach enables 'rescue' of misfolded and misrouted mutant proteins to restore function, 'shipwrecking' of undesirable proteins by targeting them for destruction, and regulation of levels of partially expressed wild type (WT) proteins at their functional sites of action. Here, we present drug discovery strategies that identify 'pharmacoperones', which are small molecules that serve as molecular templates and cause otherwise misfolded mutant proteins to fold and route correctly.
journal_name
Trends Pharmacol Scijournal_title
Trends in pharmacological sciencesauthors
Conn PM,Spicer TP,Scampavia L,Janovick JAdoi
10.1016/j.tips.2015.05.004subject
Has Abstractpub_date
2015-08-01 00:00:00pages
498-505issue
8eissn
0165-6147issn
1873-3735pii
S0165-6147(15)00094-2journal_volume
36pub_type
杂志文章,评审abstract::Exposure of cells to agonists of receptors linked to G proteins can result in downregulation of cellular levels or redistribution of G proteins from membranes to the cytosol. Agonist-induced reductions in G protein levels have been observed for members of each of the Gs, Gi and Gq families of G proteins, are likely to...
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journal_title:Trends in pharmacological sciences
pub_type: 杂志文章,评审
doi:10.1016/j.tips.2010.12.005
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journal_title:Trends in pharmacological sciences
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journal_title:Trends in pharmacological sciences
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journal_title:Trends in pharmacological sciences
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abstract::Efforts to model and reengineer the putative binding sites of G-protein-coupled receptors (GPCRs) have led to an approach that combines small-molecule 'classical' medicinal chemistry and gene therapy. In this approach, complementary structural changes (e.g. based on novel ionic or H-bonds) are made in the receptor and...
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abstract::Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51® to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza® as a treatment for spinal muscular atrophy (SMA) - highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cas...
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abstract::Clinical experience with muscarinic agonists in the symptomatic treatment of Alzheimer's disease includes studies of the effects of pilocarpine, arecoline, bethanechol, oxotremorine and RS 86. Although the results are somewhat conflicting, there is evidence that a subgroup of patients may respond with an improvement o...
journal_title:Trends in pharmacological sciences
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