Development of an Intravenously Stable Disulfide-Rich Peptide for the Treatment of Chemotherapy-Induced Neuropathic Pain.

α-conotoxins (α-Ctxs), a class of disulfide-rich conopetides, are excellent drug leads due to their small size, high selectivity, and potency for specific membrane receptors and ion channels involved in pain transmission. However, their high susceptibility to proteolytic degradation limits their therapeutic potential. In this study, we designed and synthesized a series of conformationally stable analogues of α-Ctx Mr1.

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA) receptor-coupled Ca2.

Double-network polyphenol chitosan hydrogels with instant aldehyde-β-cyclodextrin-based structure as potential for treating bacterially infected wounds.

Treatment of multiple bacterial infected wounds by eliminating bacteria and promoting tissue regeneration remains a clinical challenge. Herein, dual-network hydrogels (CS-GA/A-β-CD) with snap-structure were designed to achieve curcumin immobilization, using gallic acid-grafted chitosan (CS-GA) and aldehyde-β-cyclodextrin (A-β-CD) crosslinked. A-β-CD were able to achieve rapid dissolution (≥222.

Transport and inhibition mechanisms of the human noradrenaline transporter.

The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons. It is a pharmacological target for various antidepressants and analgesic drugs. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown.

Unraveling novel umami peptides from yeast extract (Saccharomyces cerevisiae) using peptidomics and molecular interaction modeling.

Yeast extract is increasingly becoming an attractive source for unraveling novel umami peptides that are healthier and more nutritious than traditional seasonings. In the present study, a strategy for screening novel umami peptides was established using mass spectrometry-based peptidomics combined with molecular interaction modeling, emphasizing on smaller peptides than previously reported. Four representative novel umami peptides of FE, YDQ, FQEY, and SPFSQ from yeast extract (Saccharomyces cerevisiae) were identified and validated by sensory evaluation, with thresholds determined as 0.

Rational Design of Potent α-Conotoxin PeIA Analogues with Non-Natural Amino Acids for the Inhibition of Human α9α10 Nicotinic Acetylcholine Receptors.

α-Conotoxins (α-CTxs) are structurally related peptides that antagonize nicotinic acetylcholine receptors (nAChRs), which may serve as new alternatives to opioid-based treatment for pain-related conditions. The non-natural amino acid analogues of α-CTxs have been demonstrated with improved potency compared to the native peptide. In this study, we chemically synthesized Dab/Dap-substituted analogues of α-CTx PeIA and evaluated their activity at heterologously expressed human α9α10 nAChRs.

Discovery of D25, a Potent and Selective MNK Inhibitor for Sepsis-Associated Acute Spleen Injury.

Mitogen-activated protein kinase-interacting protein kinases (MNKs) and phosphorylate eukaryotic initiation factor 4E (p-eIF4E) play a critical role in regulating mRNA translation and protein synthesis associated with the development of cancer, metabolism, and inflammation. This study undertakes the modification of a 4-(3-(piperidin-4-yl)-1-pyrazol-5-yl)pyridine structure, leading to the discovery of 4-(3-(piperidin-4-yl)-1-pyrazol-5-yl)-1-pyrrolo[2,3-]pyridine (D25) as a potent and selective MNK inhibitor. D25 demonstrated inhibitory activity, with IC values of 120.

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode.

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods.

Dual Antagonism of α9α10 nAChR and GABA Receptor-Coupled Ca2.2 Channels by an Analgesic αO-Conotoxin Analogue.

Pain severely affects the physical and mental health of patients. The need to develop nonopioid analgesic drugs to meet medical demands is urgent. In this study, we designed a truncated analogue of αO-conotoxin, named GeX-2, based on disulfide-bond deletion and sequence truncation.

JC-010a, a novel selective SHP2 allosteric inhibitor, overcomes RTK/non-RTK-mediated drug resistance in multiple oncogene-addicted cancers.

Src homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein phosphatase that transduces signals from upstream receptor tyrosine kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2.

Discovery of a pyrrole-pyridinimidazole derivative as novel SIRT6 inhibitor for sensitizing pancreatic cancer to gemcitabine.

Pancreatic cancer is a highly aggressive cancer, and is primarily treated with gemcitabine, with increasing resistance. SIRT6 as a member of sirtuin family plays important roles in lifespan and diverse diseases, such as cancer, diabetes, inflammation and neurodegenerative diseases. Considering the role of SIRT6 in the cytoprotective effect, it might be a potential anticancer drug target, and is associated with resistance to anticancer therapy.

Pathophysiology of obesity and its associated diseases.

The occurrence of obesity has increased across the whole world. Many epidemiological studies have indicated that obesity strongly contributes to the development of cancer, cardiovascular diseases, type 2 diabetes, liver diseases and other disorders, accounting for a heavy burden on the public and on health-care systems every year. Excess energy uptake induces adipocyte hypertrophy, hyperplasia and formation of visceral fat in other non-adipose tissues to evoke cardiovascular disease, liver diseases.

Molecular Dynamic Simulations Reveal the Activation Mechanisms of Oxidation-Induced TRPV1.

Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, can be directly activated by oxidants through cysteine modification. However, the patterns of cysteine modification are unclear. Structural analysis showed that the free sulfhydryl groups of residue pairs C387 and C391 were potentially oxidized to form a disulfide bond, which is expected to be closely related to the redox sensing of TRPV1.

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance.

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds , , and with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance.

Electrochemical detection of genetic damage caused by the interaction of novel bifunctional anthraquinone-temozolomide antitumor hybrids with DNA modified electrode.

In this work, novel potential anthraquinone-temozolomide (TMZ) antitumor hybrids N-(2-((9,10-dioxo-9,10-dihydroanthracen-1-yl)amino)ethyl)-3-methyl-4-oxo-3,4-dihydroimidazo [5, 1-d][1,2,3,5]tetrazine-8-carboxamide (C-1) and 2-(9,10-dioxo-9,10-dihydroanthracen-1-yl)amino) ethyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (C-9) were designed and synthesized successfully. The electrochemical behaviors of C-1 (C-9) involved the reversible processes of 9,10-anthraquinone ring, the irreversible reduction and oxidation processes of TMZ ring. Electrochemical biosensors were constructed with ctDNA, poly (dG) and poly (dA) modifying the surface of glassy carbon electrode (GCE) to evaluate the DNA oxidative damage caused by the interaction of C-1 (C-9) with DNA.

Discovery and design of dual inhibitors targeting Sphk1 and Sirt1.

Context: Leukaemia has become a serious threat to human health. Although tyrosine kinase inhibitors (TKIs) have been developed as targets for the remedy of leukaemia, drug resistance occurs. Research demonstrated that the simultaneous targeting of sphingosine kinase 1 (Sphk1) and Sirtuin 1 (Sirt1) can downregulate myeloid cell leukaemia-1 (MCL-1), overcome the resistance of tyrosine kinase inhibitors, and play a synergistic inhibitory impact on leukaemia treatment.

Peptide Stapling through Site-Directed Conjugation of Triazine Moieties to the Tyrosine Residues of a Peptide.

Peptide stapling is a strategy for improving the biological properties of peptides. Herein, we report a novel method for stapling peptides that utilizes bifunctional triazine moieties for two-component conjugation to the phenolic hydroxyl groups of tyrosine, which enables efficient stapling of unprotected peptides. In addition, we applied this strategy to the RGD peptide that can target integrins and demonstrated that the stapled RGD peptide had significantly improved plasma stability and integrin-targeting ability.

Correction to "Using Imidazo[2,1-][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors".

[This corrects the article DOI: 10.1021/acsmedchemlett.2c00442.

Electrochemical detection of the oxidative damage of a potential pyrimido[5,4-g]pteridine-derived antitumor agent toward DNA.

In this work, we design and synthesize 2,2'-(7,9-dimethyl-2,4,6,8-tetraoxo-6,7,8,9-tetrahydropyrimido[5,4-g]pteridine-1,3(2H,4H)-diyl)bis(N,N-bis(2-chloroethyl)acetamide) (PT-MCA) as a novel DNA intercalator and potential antitumor agent. Electrochemical analysis reveals the redox process of PT-MCA on the electrode surface. The bioelectrochemical sensors are obtained by modifying the surface of GCE with calf thymus DNA (ctDNA), poly (dG), poly (dA), and G-quadruplex, respectively.

Designing antimicrobial peptides using deep learning and molecular dynamic simulations.

With the emergence of multidrug-resistant bacteria, antimicrobial peptides (AMPs) offer promising options for replacing traditional antibiotics to treat bacterial infections, but discovering and designing AMPs using traditional methods is a time-consuming and costly process. Deep learning has been applied to the de novo design of AMPs and address AMP classification with high efficiency. In this study, several natural language processing models were combined to design and identify AMPs, i.

Research on named entity recognition method of marine natural products based on attention mechanism.

Marine natural product (MNP) entity property information is the basis of marine drug development, and this entity property information can be obtained from the original literature. However, the traditional methods require several manual annotations, the accuracy of the model is low and slow, and the problem of inconsistent lexical contexts cannot be solved well. In order to solve the aforementioned problems, this study proposes a named entity recognition method based on the attention mechanism, inflated convolutional neural network (IDCNN), and conditional random field (CRF), combining the attention mechanism that can use the lexicality of words to make attention-weighted mentions of the extracted features, the ability of the inflated convolutional neural network to parallelize operations and long- and short-term memory, and the excellent learning ability.

Design, synthesis, and mechanism of action of novel μ-conotoxin KIIIA analogues for inhibition of the voltage-gated sodium channel Na1.7.

μ-Conotoxin KIIIA, a selective blocker of sodium channels, has strong inhibitory activity against several Na isoforms, including Na1.7, and has potent analgesic effects, but it contains three pairs of disulfide bonds, making structural modification difficult and synthesis complex. To circumvent these difficulties, we designed and synthesized three KIIIA analogues with one disulfide bond deleted.

Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist.

Cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling stimulators, an essential innate immunity component, monitor invading pathogen DNA and damaged self-DNA, making them an appealing target for drug development. The natural STING agonist, 2'3'-cGAMP, mounts and stabilizes the STING homodimer to trigger an antiviral or antitumor immune responses. However, cyclic-dinucleotide-based STING agonists show limited clinical effects owing to their short half-lives.