137618-48-5Relevant articles and documents
A Small Molecule That Switches a Ubiquitin Ligase from a Processive to a Distributive Enzymatic Mechanism
Kathman, Stefan G.,Span, Ingrid,Smith, Aaron T.,Xu, Ziyang,Zhan, Jennifer,Rosenzweig, Amy C.,Statsyuk, Alexander V.
, p. 12442 - 12445 (2015)
E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
PH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases
Mena-Barragn, Teresa,Narita, Aya,Matias, Dino,Tiscornia, Gustavo,Nanba, Eiji,Ohno, Kousaku,Suzuki, Yoshiyuki,Higaki, Katsumi,Fernndez, Jos Manuel Garcia,Ortiz Mellet, Carmen
, p. 11696 - 11700 (2015)
A general approach is reported for the design of small-molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self-inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH-responsive glycomimetics targeting human glucocerebrosidase or α-galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed. pH-Responsive chaperones for rescuing mutant lysosomal glycosidases were developed by incorporating an acid-labile orthoester into sp2-iminosugar conjugates. In the endoplasmic reticulum (ER; pH 7), the chaperone binds to the mutant enzyme and promotes correct folding and trafficking. In the lysosome (pH 5), fast hydrolysis of the orthoester leads to inactivation of the chaperone.
Orthoester functionalized: N -guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase
Sev?ek, Alen,Sastre Tora?o, Javier,Quarles Van Ufford, Linda,Moret, Ed E.,Pieters, Roland J.,Martin, Nathaniel I.
, p. 2050 - 2054 (2017)
Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human β-glucocerebrosidase (GBA) at pH 7.0 with IC50 values in the low nanomolar range. Notably, a significant drop in inhibitory activity is observed when the same compound is tested at pH 5.2. This pH sensitive activity is due to degradation of the orthoester functionality at lower pH accompanied by loss of the alkyl group. This approach provides a degree of control in tuning enzyme inhibition based on the local pH. Compounds like those here described may serve as tools for studying various lysosomal storage disorders such as Gaucher disease. In this regard, the most active compound was also evaluated as a potential pharmacological chaperone by assessing its effect on GBA activity in an assay employing fibroblasts from Gaucher patients.
Allylamine derivative as well as preparation method and application thereof
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Paragraph 0226; 0227; 0232; 0233, (2021/06/02)
The invention relates to an allylamine derivative as well as a preparation method and application thereof, and in particular, relates to a compound represented by a formula I, or a stereoisomer, a tautomer, a polymorphic substance, a solvate, an N-oxide, an isotope labeled compound, a metabolite, a prodrug or ester thereof, or a pharmaceutically acceptable salt thereof. The compound has a higher inhibitory activity against vascular adhesion protein 1/semicarbazide sensitive amine oxidase, a good selectivity against monoamine oxidase and diamine oxidase; and additionally, in some embodiments, the mixture has a high in vivo bioavailability as well as safety.
Vinyl sulfone-based inhibitors of trypanosomal cysteine protease rhodesain with improved antitrypanosomal activities
Ajayi, Oluwatomi,Collins, Jasmine,Crown, Olamide,Nyamwihura, Rogers,Ogungbe, Ifedayo Victor,Zhang, Huaisheng
supporting information, (2020/05/18)
The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.
