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PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50values of 250 nM and 50 nM, respectively. Compound 75induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0–2hto 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Disulfide bonds are widely found in natural peptides and play a pivotal role in stabilizing their secondary structures, which are highly associated with their biological functions. Herein, we introduce a light-mediated strategy to effectively control the formation of disulfides. Our strategy is based on 2-nitroveratryl (oNv), a widely used photolabile motif, which serves both as a photocaging group and an oxidant (after photolysis). We demonstrated that irradiation of oNv-caged thiols with UV light could release free thiols that are rapidly oxidized by locally released byproduct nitrosoarene, leading to a “break-to-bond” fashion. This strategy is highlighted by the in siturestoration of the antimicrobial peptide tachyplesin I (TPI) from its external disulfide-caged analogue TPI-1. TPI-1 exhibits a distorted structure and a diminished function. However, upon irradiation, the β-hairpin structure and membrane activity of TPI were largely restored via rapid intramolecular disulfide formation. Our study proposes a powerful method to regulate the conformation and function of peptides in a spatiotemporal manner, which has significant potential for the design of disulfide-centered light-responsive systems.

ABSTRACTIntroduction: Type 2 diabetes is a rapid-growing complex chronic metabolic disease characterized by hyperglycemia due to lessened insulin secretion, insulin resistance and hepatic glucose overproduction. GPR119 is a class A of G protein-coupled receptor, expressed on certain enteroendocrine L and K cells in the small intestine and by β-cells within the islets of Langerhans of the pancreas. Activation of GPR119 stimulates the secretion of glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic β-cells.Area covered: This review summarized the reported patents on GPR119 agonists from 2014 to present. The authors described the structural features of these novel synthetic molecules and compared their biological activities (including in vitroand in vivo) as potent GPR119 agonists for the treatment of diabetes.Expert opinion: GPR119 agonists remain the advantage of stimulating both insulin and incretin release in a glucose-dependent manner over other hypoglycemic agents, although some GPR119 agonist clinical candidates have been discontinued in Phase І or Phase II. GPR119 agonists will succeed to be developed as anti-diabetic drugs after accumulated scaffolds of agonists are discovered and the crystallographic structure of GPR119 is elucidated. The synergic effect of GPR119 agonist and DPP-4 inhibitor will also elicit a benefit for the new therapeutic of diabetes.

Three compounds were obtained from Sabia parvifloraWall., and their structures were identified through nuclear magnetic resonance (NMR) spectroscopy, particularly 2-dimensional (2D)-NMR. The molecular masses were determined using quadrupole-time-of-flight-mass spectrometry. Electronic circular dichroism spectra were used to determine the absolute configuration of compound 1. The 3 new compounds were identified as 2,2,7,7-tetramethyl-8S,10-dihydroxy-2,7,8,9-tetrahydro-2H-naphtha[2,3-b]pyran-6-one-10-O-β-D-glucopyranoside, (2Z)-4-(3-carboxy-4-hydroxyphenyl)-2-methylbut-2-enoic acid, and (2Z)-5-(3-carboxy-4-hydroxyphenyl)-5-oxo-2-methylpent-2-enoic acid. The liver protective activities of these compounds were tested by HepG2 and LO2 cell lines, which were induced using free fatty acids.

Farnesoid X receptor (FXR) is an important regulator of bile acid, lipid, amino acid, and glucose homeostasis, hepatic inflammation, regeneration, and fibrosis. FXR has been recognized as a promising drug target for various metabolic diseases such as lipid disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic kidney disease. A large number of FXR ligands have been developed by pharmaceutical companies and academic institutions, and several candidates have progressed into clinical trials in the past decade. However, it is continually a challenge to discover drugs targeting FXR due to side effects associated with long-term administration. In this perspective, we summarize the research progress on medicinal chemistry of FXR modulators from 2018 to the present by discussing the diverse structures of synthetic FXR modulators including steroidal and non-steroidal ligands, their structure–activity relationships (SARs), and their therapeutic applications.