The halophyte Eutrema salsugineum is naturally distributed in saline-alkali soil and has been proposed as a model plant for understanding plant salt tolerance. As one of the largest and most diverse TF families, basic leucine zipper motif (bZIP) TFs perform robust functions in plant growth and environmental response, however the generalized information of EsbZIP genes and its regulatory role in salt tolerance has not been systematically studied to date. Here, we identified and characterized the bZIP members in E.
View Article and Find Full Text PDFBreast cancer, the most prevalent malignancy among women, frequently exhibits high HER2 expression, making HER2 a critical therapeutic target. Traditional treatments combining the anti-HER2 antibody trastuzumab with immunotherapy face limitations due to toxicity and tumor microenvironment immunosuppression. This study introduces an innovative strategy combining HER2-targeting peptides with the photosensitizer (PSs) pyropheophorbide-a (Pha) via a gelatinase-cleavable linker, forming self-assembling nanoparticles.
View Article and Find Full Text PDFClin Exp Pharmacol Physiol
December 2024
Evodiamine is a biologically active alkaloid extracted from the fruit of the traditional Chinese medicine Evodia rutaecarpa (Juss.) Benth. (Fructus Evodiae, Wuzhuyu).
View Article and Find Full Text PDFSmall molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity.
View Article and Find Full Text PDFProteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer-PROTAC conjugation approach is developed to enhance tumor targeting and antitumor potency. Specifically, a smart prodrug is designed by conjugating "drugtamer" to a nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using a tumor microenvironment responsible linker.
View Article and Find Full Text PDFAntimicrobial photodynamic therapy (PDT) is a promising alternative to antibiotics for eradicating pathogenic bacterial infections. It holds advantage of not inducing antimicrobial resistance but is limited for the treatment of gram-negative bacterial infection due to the lack of photosensitizer (PS) capable of targeted permeating the outer membrane (OM) of gram-negative bacteria. To facilitate the targeted permeability of PS, cyclic polymyxin b nonapeptide that can specifically bind to the lipopolysaccharide on OM, is conjugated to an FDA approved PS chlorin e6 via variable linkers.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
March 2024
Nicotinamide adenine dinucleotide (NAD ) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme involved in NAD biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD in biological systems using photoswitchable proteolysis-targeting chimeras (PS-PROTACs).
View Article and Find Full Text PDFProteolysis-targeting chimeras (PROTACs) have recently emerged as a promising technology for drug development. However, poor water solubility, limited tissue selectivity, and inadequate tumor penetration pose significant challenges for PROTAC-based therapies in cancer treatment. Herein, we developed an iRGD-PROTAC conjugation strategy utilizing tumor-penetrating cyclic peptide iRGD (CRGDK/RGPD/EC) to deliver PROTACs deep into breast cancer tissues.
View Article and Find Full Text PDFThe identification of novel candidate molecules with the potential to revolutionize the treatment of breast cancer holds profound clinical significance. Macropin (Mac)-1, derived from the venom of wild bees, emerges as an auspicious therapeutic agent for combating breast cancers. Nevertheless, linear peptides have long grappled with the challenges of traversing cell membranes and succumbing to protease hydrolysis.
View Article and Find Full Text PDFBackground: Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression.
View Article and Find Full Text PDFHeterostructures comprising lanthanide-doped upconversion nanoparticles (DUCNPs) and metal-organic frameworks (MOFs) are emerging as promising nanosystems for integrating medical diagnosis and treatment. Here, the DUCNP@Mn-MOF nanocarrier was developed, which showed good efficiency for loading and delivering a cytotoxic antitumor agent (3-F-10-OH-evodiamine, FOE). The combined advantages of the pH-responsive and peroxidase-like properties of Mn-MOF and the unique optical features of DUCNPs granted the DUCNP@Mn-MOF/FOE system synergistic chemodynamic and chemotherapeutic effects.
View Article and Find Full Text PDFNicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies.
View Article and Find Full Text PDFObjectives: Liver cancer stem cells (LCSCs) are regarded as the frequent cause of hepatocellular carcinoma (HCC) relapse and therapeutic resistance. The epithelial cell adhesion molecule (EpCAM) is one of the key biomarkers for LCSCs. EpCAM cells from HCC have been reported to display cancer stem cell-like (CSC-like) properties.
View Article and Find Full Text PDFProteolysis-targeting chimera (PROTAC) is emerging as a promising technology in targeted protein degradation and drug discovery. However, there is still a lack of effective chemical tools to real-time detect and track the protein degradation. Herein, the first fluorescent and theranostic PROTACs were designed for imaging the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells.
View Article and Find Full Text PDFThe non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the non-enzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation.
View Article and Find Full Text PDFTargeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the application of conventional PROTACs is limited to protein targets containing cytosolic domains with ligandable sites. Recently, nucleic-acid-based modalities, such as modified oligonucleotide mimics and aptamers, opened new avenues to degrade protein targets and greatly expanded the scope of TPD.
View Article and Find Full Text PDFOxidative stress and inflammation were considered to be the major mechanisms in liver damage caused by clofibrate (CF). In order to obtain lipid-lowering drugs with less liver damage, the structure of clofibrate was optimized by O-desmethyl anetholtrithione and got the target compound clofibrate-O-desmethyl anetholtrithione (CF-ATT). CF-ATT significantly reduced the levels of plasma triglycerides (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR-1339.
View Article and Find Full Text PDFAs a promising targeted drug delivery system, aptamer-drug conjugates (ApDCs) can specifically bind with cognate molecular targets for improving therapeutic efficacy and reducing drug toxicity. However, current ApDC strategies suffer from problems caused by the complicated synthesis, relatively high cost, low controllability of drug binding sites and loading ratio. To solve these difficulties, we have designed and synthesized an artificial pharmaceutical solid-phase module of Combretastatin A-4 (CA-4), in which an inactive ingredient was selected as bonding moiety to incorporate with solid phase functionalities.
View Article and Find Full Text PDFA visible-light-driven cascade radical cyclization process of -methacryloyl-2-phenylbenzimidazole has been established with α-carbonyl alkyl bromide. This protocol provides an efficient and practical method for the synthesis of various α-carbonyl alkyl-substituted benzimidazo[2,1-]isoquinolin-6(5)-ones in outstanding yields, mild reaction conditions and excellent functional group tolerance.
View Article and Find Full Text PDFB1-Leu peptide is a structural optimization compound derived from the lysine- and phenylalanine-rich antimicrobial peptide Cathelicidin-BF. It has shown promising antibacterial and antitumor biological activity. However, linear peptides are not the best choice for novel drug development due to their poor pharmacokinetic properties.
View Article and Find Full Text PDF13-Aminomethyl-15-thiomatrine (M19) previously developed by our research group was a promising candidate for novel anti-osteoporosis drug development. However, the application of M19 was limited by its unsatisfactory druggability including poor chemical stability, excessively broad pharmacological activity and some degree of cytotoxicity. To solve these problems, M19-based bone targeting and cathepsin K sensitive peptide-drug conjugates (BTM19-1, BTM19-2 and BTM19-3) were developed to realize precise drug release in the bone tissue.
View Article and Find Full Text PDFPancreatic carcinoma (PC) has one of the highest mortality-to-incidence ratios of any solid tumor worldwide. Although KRAS mutation is commonly found in 95% of PCs, directly targeting KRAS remains to be a highly challenging task because of its lacking catalytic pockets where molecule inhibitors can bind with. Proteolysis-targeting chimeric (PROTAC) represents an effective approach for specific degradation of disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system (UPS).
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