Using pharmacological chaperones to restore proteostasis

Extracellular chaperones and proteostasis.

There exists a family of currently untreatable, serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited, but it has significantly advanced with the discovery of a small but growing family of constitutively secreted extrac...

Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity.

Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations functionally characterized so far lead to intracellular retention of receptors by the cell's quality control system. Thus, recovering cell surface expressio...

Supplemental Data Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity

Ribosome-associated chaperones act as proteostasis sentinels

*Correspondence to: Richard I. Morimoto; Email: [email protected] Submitted: 05/30/2013; Accepted: 06/03/2013 http://dx.doi.org/10.4161/cc.25703 Comment on: Kirstein-Miles J, et al. EMBO J 2013; 32:1451-68; PMID:23604074; http://dx.doi.org/10.1038/emboj.2013.87 The production of newly synthesized proteins is a key process of protein homeostasis that initiates the biosynthetic flux of ...

Pharmacological Chaperones by Design

One of the most successful approaches in the synthesis of inhibitors of t he g lycosidases i s t he s ubstitution of t he e ndocyclic ox ygen i n monosaccharides by a nitrogen atom to get iminosugars. Given that many diseases h ave t heir o rigin i n t he malfunctioning of t hese e nzymes, t his glycomimetics bear s trong p otential a s dr ug c andidates. A t th eir p rotonated state, iminosuga...