Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

Author correction to"Coordinated regulation of BACH1 and mitochondrial metabolism through tumor targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy"[Acta Pharmaceutica Sinica B 12(2022)3934-3951]

The authors regret that there are two errors in the article Fig.4A and Fig.5C due to the mistake of copying and pasting in the process of assembling figures and negligence in the proofreading.

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy

The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overall survival.Here we developed a strategy by employing tumor-targeted selfassembled nanoparticles to coordinately regulate BACH1(BTB domain and CNC homology 1)and mitochondrial metabolism.The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative(BD)were used to prepare nanoparticles(BH NPs)followed by the modification of chondroitin sulfate(CS)on the surface of BH NPs to achieve tumor targeting(CS/BH NPs).CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites,glycolysis and metastasis-associated proteins,which were related to the inhibition of BACH1 function.Meanwhile,decreased mitochondrial membrane potential,activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism.In a xenograft mice model of breast cancer,CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs.In sum,the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

Gold-catalyzed ketene dual functionalization and mechanistic insights:divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed.Mechanistic studies and density function theory(DFT)calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate,followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates.In the case with alcohols as the nucleophiles,the reaction goes through a C-5-endodig carbocyclization to give the indene products;whereas,O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles,delivering the 7-membered benzo[d]oxepines.In comparison with the well-documented cycloaddition and nucleophilic addition reactions,this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.

Chiral rhodium(Ⅱ)-catalyzed asymmetric aldol-type interception of an oxonium ylide to assemble chiral 2,3-dihydropyrans

A chiral dirhodium complex is an effective and robust catalyst for asymmetric carbene transformations.However,dirhodiumcatalyzed asymmetric ylide interception processes are rare,mainly because of the dissociation of the metal catalyst before the stereo-determining step.Herein,we report a chiral dirhodium(Ⅱ)-catalyzed asymmetric annulation of vinyl diazoesters withα-hydroxyl ketones,which provides an efficient way to form chiral 2,3-dihydropyrans in good yields with excellent diastereoselectivities and enantioselectivities.This article is the first example of the chiral dirhodium complex–controlled asymmetric aldol-type interception of an in situ–formed oxonium ylide.The origin of the high stereoselectivity is well expounded via experimental and computational studies.These generated chiral products exhibit potent antiproliferation activity in three tested cancer cell lines,namely HCT116(colon cancer),A549(lung adenocarcinoma),and SJSA-1(osteosarcoma cancer).

Asymmetric Three-Component Propargyloxylation for Direct Assembly of Polyfunctionalized Chiral Succinate Derivatives

An enantioselective three-component propargyloxylation reaction of propargyl alcohols,pyridotriazoles,and imines has been realized by cooperative catalysis with dirhodium complex and chiral phosphoric acid under mild conditions.This is the first example of a catalytic asymmetric three-component propargyloxylation reaction,which provides practical access to chiral polyfunctionalized succinate derivatives with adjacent quaternary and tertiary stereocenters in good to high yields with excellent enantioselectivity.In addition to the alkyne motif,pyridyl,alkoxy,amino,and alkenyl species are all tolerated under the reaction conditions.Notably,the utility of the current method is demonstrated by catalytic cyclization of the product alkyne into a variety of heterocyclic structures without loss of enantiomeric purity.

Recent progress in the synthesis of sulfonyl fluorides for SuFEx click chemistry

Since the sulfur(Ⅵ)fluoride exchange reaction(SuFEx)was introduced by Sharpless and co-workers in 2014,this new-generation click chemistry has emerged as an efficient and reliable tool for creating modular intermolecular connections.Sulfonyl fluorides,one of the most important sulfur(Ⅵ)fluoride species,have attracted enormous attention in diverse fields,ranging from organic synthesis and material science,to chemical biology and drug discovery.This review aims to introduce seminal and recent progresses on the synthetic methods of sulfonyl fluorides,which include aromatic,aliphatic,alkenyl,and alkynyl sulfonyl fluorides.While not meant to be exhaustive,the purpose is to give a timely overview and insight in this field,and stimulate the development of more efficient synthetic methods of sulfonyl fluorides.

Synthesis of difluoromethylated benzylborons via rhodium(Ⅰ)-catalyzed fluorine-retainable hydroboration of gem-difluoroalkenes

The synthesis of bo rylated orga nofluorines is of great interest due to their potential values as synthons in modular construction of fluorine-containing molecules.Reported herein is a rhodium-catalyzed hydrobo ration of arylgem-difluoroalkenes leading to a series of α-difluoromethylated benzylborons.The use of cationic rhodium catalyst and a biphosphine ligand with large bite angle was crucial for reactivity by offering good regioselectivity and diminishing the undesired β-F elimination.Preliminary derivatizations of the products were conducted to showcase the utility of this protocol.

Multi-functional vesicles improve Helicobacter pylori eradication by a comprehensive strategy based on complex pathological microenvironment

Helicobacter pylori(H.pylori),creating a global infection rate over 50%,presents great challenges in clinical therapies due to its complex pathological microenvironment in vivo.To improve the eradication efficacy,herein we fabricated a pharmaceutical vesicle RHL/Cl-Ch-cal where cholesterol-PEG,calcitriol and first-line antibiotic clarithromycin were co-loaded in the rhamnolipid-composed outer lipid layer.RHL/Cl-Ch-cal could quickly penetrate through gastric mucus layer to reach H.pylori infection sites,and then effectively destroyed the architecture of H.pylori biofilms,killed dispersed H.pylori and inhibited the re-adhesion of residual bacteria(called biofilms eradication tetralogy).Moreover,RHL/Cl-Ch-cal activated the host immune response to H.pylori by replenishing cholesterol to repair lipid raft on the cell membrane of host epithelial cells.Finally,RHL/Cl-Ch-cal killed the intracellular H.pylori through recovering the lysosomal acidification and assisting degradation.In experiments,RHL/Cl-Ch-cal demonstrated prominent anti-H.pylori efficacy in the classical H.pylori-infected mice model.Therefore,the study provides a“comprehensive attack”strategy for anti-H.pylori therapies including biofilms eradication tetralogy,immune activation and intracellular bacteria killing.

A multifunctional cholesterol-free liposomal platform based on protopanaxadiol for alopecia therapy

Liposome could form a long-term drug reservoir in the skin for sustained drug release,which is beneficial to improving efficacy and alleviating adverse effects.Thus,it has become a better option for anti-alopecia drugs delivery.However,cholesterol used as the fluidity buffer in conventional liposomes is a precursor for testosterone biosynthesis,which could convert to dihydrotestosterone,resulting in hair follicle damage and potentiating hair loss.To overcome the limitations,in this study we prepared a cholesterol-free liposome(PPD-Lip)using protopanaxadiol(PPD)instead of cholesterol to avoid the biosynthesis of testosterone which is adverse to alopecia therapy.PPD-Lip also worked as an active ingredient to facilitate hair growth by promoting dermal papilla cells proliferation and migration,upregulating mRNA levels of hair growth-related positive regulators,and accelerating angiogenesis in vitro.Meanwhile,it promoted hair regrowth in telogen and androgenetic alopecia mice models in vivo.In addition,our study showed that as the liposomal vehicle,PPD-Lip loaded with dutasteride exerted a stronger efficacy in the treatment of androgenetic alopecia and such a strategy could extend to other anti-alopecia agents.To the best of our knowledge,being easy for clinical transformation,the PPD-based liposomal delivery system provides a promising and multifunctional alternative platform for the delivery of alopecia treatment agents.