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A highly oriented poly(l-lactic acid) (PLLA), with a blood vessel-like biomimetic structure, was fabricated using solid-phase hot drawing technology and homo-epitaxial crystallization to improve the mechanical properties and biocompatibility of PLLA. Long chain branched PLLA (LCB-PLLA) was prepared through a two-step ring-opening reaction, and a consequent draw as high as 1000 % was achieved during the hot drawing. The modulus and tensile strength were found to have increased through the formation of oriented shish-kebab like crystals along the drawing direction during processing. Furthermore, PLLA nano-lamellae were formed on the surface of the oriented plates via the introduction of homo-epitaxial crystallization. The high degree of orientation and epitaxial crystallization substantially enhanced the biocompatibility of the PLLA by prolonging clotting time, decreasing the rate of hemolysis, and increasing the cell growth and reproduction of the osteoblasts.

Chemical proteomics is a powerful technology that can be used in the studies of the functions of uncharacterized proteins in the human proteome. It relies on a suitable bioconjugation strategy for protein labeling. This could be either a UV-responsive photo-crosslinker or an electrophilic warhead embedded in chemical probes that can form covalent bonds with target proteins. Here, we report a new protein-labeling strategy in which a nitrile oxide, a highly reactive intermediate that reacts with proteins, can be efficiently generated by the treatment of oximes with a water-soluble and a minimally toxic oxidant, phenyliodine bis (trifluoroacetate) (PIFA). The resulting intermediate can rapidly bioconjugate with amino acid residues of target proteins, thus enabling target identification of oxime-containing bioactive molecules. Excellent chemoselectivity of cysteine residues by the nitrile oxide was observed, and over 4000 reactive and/or accessible cysteines, including KRAS G12C, have been successfully characterized by quantitative chemical proteomics. Some of these residues could not be detected by conventional cysteine reagents, thus demonstrating the complementary utility of this method.

Poly(l-lactic acid) (PLLA) displays simultaneous repair and regeneration properties. Therefore, it is vital for developing bone repair materials while improving their mechanical strength, and biocompatibility is essential for guaranteeing its application. In this manuscript, using solid hot drawing (SHD) technology to fabricate an oriented shish-kebab like structure, furthermore, the interface-oriented grain boundary controlled the nucleation site and cell morphology during low temperature supercritical carbon dioxide (SC-CO

[Image: see text] Innovation in medicinal chemistry has been at the heart of ACS Medicinal Chemistry Letters since the journal’s founding 10 years ago. In his inaugural editorial, Editor-in-Chief Dennis Liotta laid out a vision for the journal to become the “premier international journal for rapid communication of cutting-edge studies,” and, after 10 years, it has become exactly that. The great hope of drug discovery scientists is that their innovations will lead to new therapeutics to treat unmet medical needs. In the spirit of innovation and in celebration of the recent 10th anniversary of ACS Med. Chem. Lett., we highlight five therapeutics that were first reported or first comprehensively characterized within ACS Med. Chem. Lett.. This overview also serves to introduce the expansion of the scope of the Innovations article type to include Topical Innovations. With this extension, the journal hopes to provide a forum to showcase concise (rather than comprehensive) reviews of topics that are both timely and of great interest to the medicinal chemistry community. Moreover, these articles will emphasize the next steps to move the field toward new areas of interest in medicinal chemistry. Appropriate topics might include case studies of clinical candidates or approved drugs, new assay technologies in drug discovery, novel target classes, and innovative new approaches towards modulation of human physiology. Since its founding 10 years ago, ACS Med. Chem. Lett. has established itself as a venue for the rapid communication of studies in medicinal chemistry and drug discovery. There have been several drugs and clinical candidates that were first reported or first comprehensively characterized in ACS Med. Chem. Lett. In celebration of the 10th anniversary of ACS Med. Chem. Lett. this Topical Innovations article highlights five of these compounds: Ivosidenib, Siponimod, Glasdegib, Parsaclisib, and Dabrafenib.

The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently modify a triple-negative breast cancer driver, glutathione S-transferase pi-1 (GSTP1), by covalently binding at the catalytic active site. Further structure optimization and signaling pathway validation have led to the discovery of potent inhibitors of GSTP1.

Thiols are important units in amino acids such as cysteine and peptides like glutathione. Development of chemical sensors capable of precise detection of thiols is important in cancer diagnosis and therapy. We have developed novel two-photon fluorescent turn-on probes for selective detection of thiols. The probes displayed excellent sensitivity and low detection limits. The dual-purpose probes have been demonstrated to be suitable for simultaneous imaging and proteome profiling in live cells and tumor tissues. The unique turn-on design endows the probes with excellent selectivity toward thiols in vitro and in situ, and can be further developed to support a thiol-quantification assay.

This study employed solid hot stretching technology to produce successfully specifically oriented polylactic acid (PLA) while investigating the impact of orientation structure on its photo-oxidation aging properties. After orientation, the molecular weight and mechanical properties retention rate of PLA were improved, and the crystallinity (Xc) increased in conjunction with prolonged aging time, while the molecular orientation failed to modify the mechanism responsible for PLA deterioration. Furthermore, an examination regarding the way in which the photo-oxidation stability of PLA was enhanced, demonstrated that the increased Xc and structural orientation were beneficial for delaying the photo-oxidation aging of PLA.

Competitive proteome profiling is a powerful approach for the identification of targets of small molecules. This approach usually employs an inhibitor-derived probe or a cysteine-reactive probe such as an IA-alkyne in a comparison between inhibitor-treated and untreated samples, thus enabling distinction between genuine targets and nonspecific labeling. We have developed an active probe derived from an EGFR inhibitor, afatinib, and a cysteine reactive probe, an alkyne-containing α,β-unsaturated amide, to compare their characterization of cellular targets. In both approaches, myosin heavy chain 9 (MYH9) was identified as an off-target. Subsequent functional validation experiments suggested that MYH9 might be involved in the function of afatinib.

Obesity is positively correlated with a variety of metabolic disorders. Autophagy is the major recycling process in adipocytes, dynamically regulating adipogenesis, lipid mobilization, and browning. miRNAs, a class of endogenous small noncoding RNAs, participate in each step of autophagy. Autophagy-regulating miRNAs are crucial for lipid homeostasis and proper adipocyte functioning. Herein, we summarize our current understanding of autophagy-regulating miRNAs related to obesity, as well as their specific targets. Autophagy-regulating miRNAs might fill crucial gaps in our understanding of the nature of obesity and provide promising targets for the diagnosis and treatment of obesity-related metabolic disorders.

Covalent inhibitors with an electrophilic warhead have received considerable attention due to their remarkable pharmacological properties. However, the electrophilic warhead in covalent drugs is often an α, β-unsaturated amide, and the targets are mainly cysteine or lysine residues. Thus, the development of novel electrophiles that can target other amino acids is highly desirable. Ynamide, a useful and versatile building block, is commonly employed in the construction of various compounds in organic synthesis. The performance of this functional group in a proteome-wide environment has been studied here for the first time, and it has been shown that it can efficiently modify carboxyl residues in situ and in vitro. Upon incorporation of this ynamide warhead into the pharmacophores of kinase inhibitors, the resulting compound showed moderate inhibition against the EGFR L858R mutant but not against EGFR WT. This novel electrophilic group can be used in the development of new types of covalent inhibitors.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound

Protein modification by chemical reagents has played an essential role in the treatment of human diseases. However, the reagents currently used are limited to the covalent modification of cysteine and lysine residues. It is thus desirable to develop novel methods that can covalently modify other residues. Despite the fact that the carboxyl residues are crucial for maintaining the protein function, few selective labeling reactions are currently available. Here, we describe a novel reactive probe, 3-phenyl-2H-azirine, that enables chemoselective modification of carboxyl groups in proteins under both in vitro and in situ conditions with excellent efficiency. Furthermore, proteome-wide profiling of reactive carboxyl residues was performed with a quantitative chemoproteomic platform.

[Image: see text] Target identification of small molecules is a great challenge but an essential step in drug discovery. Here, a quantitative proteomics approach has been used to characterize the cellular targets of DR, a DDR1 inhibitor. By taking advantage of competitive affinity-based protein profiling coupled with bioimaging, Cathepsin D (CTSD) was found to be the principle off-target of DR in human cancer cells. Further findings suggest the potential of DR as a novel CTSD inhibitor for breast cancer treatment. In addition, a trans-cyclooctene (TCO) containing probe was developed to track the binding between DR and its target proteins in living systems and could be a useful tool for DDR1 detection.

[Image: see text] Target identification is an essential step in drug discovery. It facilitates an understanding of drug action and potential toxicities and offers opportunities to repurpose drug candidates. HP-1, a potent EGFR(L858R/T790M) (epidermal growth factor receptor) mutant inhibitor, was developed by the group in an effort to treat acquired resistance in nonsmall cell lung cancer (NSCLC), but its cellular off-targets were not identified. An activity-based probe, HJ-1, was created followed by chemical proteomics and bioimaging studies. A total of 13 protein hits, including EGFR and NT5DC1, were identified by pull-down/LC-MS. Subsequent validation experiments indicated the involvement of a major off-target, NT5DC1, in the biological function of HP-1.

In this study, preoperative analysis of 1106 gastropathy patients with abdominal pain, vomiting, dyspepsia, and other symptoms was conducted. Independent sample t -test and correlation analysis and other ways were used for data cleansing and analysis. Findings were as follows: (1) Samples of different genders showed significance in PGI and PGII. The PGI and PGII values of women were significantly lower than those of men. (2) Age showed a significant positive correlation with PGI and PGII, which indicates that as the age increases, the PGI and PGII values become higher. (3) There was a significant negative correlation between age and abdominal pain. This signified that the younger the patient is, the more likely they will suffer abdominal pain. (4) PGI displayed a positive correlation with abdominal pain in the digestive tract (dyspepsia, gastrointestinal ulcers, gastrointestinal bleeding, etc.). It indicated that the higher the PGI value is, the more likely the patients will suffer abdominal pain and gastrointestinal diseases (dyspepsia, gastrointestinal ulcer, gastrointestinal hemorrhage, etc.). (5) PGII displayed a significant positive correlation with gastrointestinal diseases (dyspepsia, gastrointestinal ulcer, gastrointestinal hemorrhage, etc.) and a negative correlation with gastropathy (acute gastritis, chronic superficial gastritis, gastric ulcer, etc.). It indicated that the higher the value of PGII is, the more likely the patients will suffer symptoms of gastrointestinal diseases (dyspepsia, gastrointestinal ulcer, gastrointestinal hemorrhage, etc.), while less likely the patients will suffer gastropathy (acute gastritis, chronic superficial gastritis, gastric ulcer, etc.).

Low-grade chronic adipose tissue inflammation contributes to the onset and development of aging-related insulin resistance and type 2 diabetes. In the current study, α-mangostin, a xanthone isolated from mangosteen (Garcinia mangostana), was identified to ameliorate lipopolysaccharides-induced acute adipose tissue inflammation in mice, by reducing the expression of pro-inflammatory cytokines and chemokines. In a cohort of young (3 months) and old (18–20 months) mice, α-mangostin mitigated aging-associated adiposity, hyperlipidemia, and insulin resistance. Further study showed that α-mangostin alleviated aging-related adipose tissue inflammation by reducing macrophage content and shifting pro-inflammatory macrophage polarization. Moreover, α-mangostin protected the old mice against liver injury through suppressing the secretion of microRNA-155-5p from macrophages. The above results demonstrated that α-mangostin represents a new scaffold to alleviate adipose tissue inflammation, which might be a novel candidate to treat aging-related metabolic disorders.

Toxin EsaD secreted by some S. aureus strains through the type VII secretion system (T7SS) specifically kills those strains lacking the antitoxin EsaG. Here we report the structures of EsaG, the nuclease domain of EsaD and their complex, which together reveal an inhibition mechanism that relies on significant conformational change of the toxin. To inhibit EsaD, EsaG breaks the nuclease domain of EsaD protein into two independent fragments that, in turn, sandwich EsaG. The originally well-folded ββα-metal finger connecting the two fragments is stretched to become a disordered loop, leading to disruption of the catalytic site of EsaD and loss of nuclease activity. This mechanism is distinct from that of the other Type II toxin-antitoxin systems, which utilize an intrinsically disordered region on the antitoxins to cover the active site of the toxins. This study paves the way for developing therapeutic approaches targeting this antagonism.

Henoch-Schonlein purpura (HSP) is the most common childhood vasculitis, infection is the most essential inducement. We hypothesized that infection could impact the blood routine characteristics and/or outcome of vasculitis. Thus, we aim to find the most common infectious agent in HSP patients and identify convenient indicators to predict renal involvement in HSP patients with infection.We conducted a retrospective study of 208 HSP children and 98 healthy children. Clinical parameters were compared in those cases.A total of 68.75% of patients were infected with various pathogens. The mean platelet volume (MPV) (P 0.02) was lower in HSP patients with infection than patients without infection. Mycoplasma pneumoniae (MP) infection accounted for the largest proportion (45.77%). MPV in HSP nephritis (HSPN) group was lower than in HSP patients (excluded renal involvement) in patients with MP infection. Logistic regression analysis found that age and MPV were risk factors for the occurrence of MP-infected HSPN. The receiver operating characteristic curve (ROC) analysis showed that the combination of MPV with the onset age at the optimal cut-off point had 81% sensitivity in predicting whether HSP patients with MP infection would develop into HSPN.Our research revealed that MP was the most commonly infected pathogen of children's HSP. MPV was an essential predictor of nephritis in HSP patients with MP infection. This discovery can prompt clinical treatments as well as reduce costs. Key Points • Mycoplasma pneumoniae (MP) accounts for the largest proportion in HSP children with infection. • MPV can be used as a predictor for the development of MP-triggered HSP to HSPN.

Epitaxial crystallization and solid hot-drawing technology were employed to fabricate oriented homo-epitaxial crystallization of polylactic acid (PLA) with nano-topography to enhance its blood compatibility and mechanical characteristics as blood-contacting medical devices. The process involved solid hot stretching the PLA plates. A PLA nutrient solution was then used to immerse the oriented plates to dissolve some of the PLA solutes, ensuring plate integrity. Consequently, the drawing process exponentially enhanced the modulus and tensile strength of the PLA. Orientation and epitaxial crystallization could substantially enhance blood compatibility of PLA by prolonging clotting time and decreasing hemolysis rate, protein adsorption, and platelet activation. The oriented homo-epitaxial crystallization of PLA exhibited a nano-topography and fibrous structure similar to the intimal layer of a blood vessel, and this biomimetic structure was advantageous in decreasing the activation and/or adhesion of platelets.

Affinity-based protein profiling has proven to be a powerful method in target identification of bioactive molecules. Here, this technology was applied in two photoreactive anticancer inhibitors, arenobufagin and HM30181. Using UV irradiation, these photoreactive reagents can covalently cross-link to target proteins, leading to a covalent binding with target proteins. Moreover, the cellular on/off targets of these two molecules, including ATP1A1, MDR1, PARP1, DDX5, NOP2, RAB6A, and ERGIC1 were first identified by affinity-based protein profiling and bioimaging approaches. The protein hit, PARP1, was further validated to be involved in the function of the anticancer effects.

Long-chain branched poly (lactic acid) (LCB-PLA) with antimicrobial functional group was fabricated through a two-step ring-opening reactive processing for improving antimicrobial properties and broadening the PLA processing window. A combination of linear viscoelasticity and the branch-on-branch (BOB) model predicted probable compositions and chain topologies of the products. It is also explored the antimicrobial properties of LCB-PLA to provide a theoretical basis for broadening the possible applications.

To development biomimetic strategy for enhanced cancer therapy, the paclitaxel loaded egg white/sodium alginate nanoparticles were prepared by electronic spray method. Their appearance and particle size were observed by transmission electron microscope and particle size analyzer. The drug release behavior of nanoparticles was determined by high performance liquid chromatography (HPLC). The toxicity, morphology and interaction of nanoparticles to cells were studied by means of MTT, live/dead staining and laser scanning confocal microscopy. The results show that the nanoparticles have good particle size dispersion, regular morphology, good drug release performance, good biocompatibility and in vitro effective inhibition of CT26 colorectal cancer cells. These results demonstrated that the good biocompatibility of egg white coated sodium alginate nanoparticles and PTX loaded these nanoparticles would show potential application for cancer therapy.

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

AXL has been defined as a novel target for cancer therapeutics. However, only a few potent and selective inhibitors targeting AXL are available to date. Recently, our group has developed a lead compound, 9im, capable of displaying potent and specific inhibition of AXL. To further identify the cellular on/off targets, in this study, competitive affinity-based proteome profiling was carried out, leading to the discovery of several unknown cellular targets such as BCAP31, LPCAT3, POR, TM9SF3, SCCPDH and CANX. In addition, trans-cyclooctene (TCO) and acedan-containing probes were developed to image the binding between 9im and its target proteins inside live cells and tumor tissues. These probes would be useful tools in the detection of AXL in various biosystems.

Highly oriented long-chain-branched poly(lactic acid) (LCB-PLA) was fabricated through solid die drawing technology for the purpose of further improving the mechanical properties and biocompatibility of PLA as bone fixation materials. Compared with neat PLA, higher draw ratio can be obtained for LCB-PLA during the drawing process, which led to the sharp increase of the mechanical properties of PLA samples. For LCB-PLA sample with 13.2 of draw ratio, the tensile strength and modulus reached up to 235.4 MPa and 8.2 GPa, respectively, which satisfied the requirement of the weight-bearing implant fixation. The MTT and ALP results suggested that the proliferation, differentiation and ALP activity of osteoblasts on the surface of PLA samples increased with draw ratio. In addition, cells with flat and extension morphology adhered and grew better, and the spreading area of cells on LCB-PLA samples was larger than that on PLA samples, which suggested that long chain branching and uniaxial orientation exhibited optimal role in promoting cell growth and maintaining their morphology. After orientation, due to the increase of crystallinity and CH3 content on the sample surface, the hydrophobicity increased, promoting the protein adsorption and thus the cell adhesion on it; moreover, cell adhered more stably on the C O enriched and grooved surfaces of the oriented samples, further improving the cell reproduction and aggregation.