Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Progress of researches on mechanisms of acupuncture underlying improvement of cerebral ischemia-reperfusion injury by regulating calcium overload. / é’ˆåˆºè°ƒæŽ§è„‘ç¼ºè¡€å†çŒæ³¨æŸä¼¤åŽé’™è¶ è½½æœºåˆ¶ç ”ç©¶è¿›å±•.

Ischemic stroke is currently the most common type of stroke, and the key pathological link is cerebral ischemia-reperfusion injury (CIRI), while the key factor leading to apoptosis and necrosis of ischemic nerve cells is calcium overload. Current studies have confirmed that acupuncture therapy has a good modulating effect on calcium homeostasis and can reduce cerebral ischemia-reperfusion induced damage of neuronal cells by inhibiting calcium overload. After reviewing the relevant literature published in the past 15 years, we find that acupuncture plays a role in regulating the pathological mechanism of calcium overload after CIRI by inhibiting the opening of connexin 43 hemichannels, regulating the intracellular free calcium ion concentration, suppressing the expression of calmodulin, and blocking the function of L-type voltage-gated calcium channels, thereby inhibiting calcium overload, regulating calcium homeostasis and antagonizing neuronal damage resulted from cerebral ischemia-reperfusion, which may provide ideas for future research.

An electronic voting scheme based on homomorphic encryption and decentralization.

Compared with paper-based voting, electronic voting not only has advantages in storage and transmission, but also can solve the security problems that exist in traditional voting. However, in practice, most electronic voting faces the risk of voting failure due to malicious voting by voters or ballot tampering by attackers. To solve this problem, this article proposes an electronic voting scheme based on homomorphic encryption and decentralization, which uses the Paillier homomorphic encryption method to ensure that the voting results are not leaked until the election is over. In addition, the scheme applies signatures and two layers of encryption to the ballots. First, the ballot is homomorphically encrypted using the homomorphic public key; then, the voter uses the private key to sign the ballot; and finally, the ballot is encrypted using the public key of the counting center. By signing the ballots and encrypting them in two layers, the security of the ballots in the transmission process and the establishment of the decentralized scheme are guaranteed. The security analysis shows that the proposed scheme can guarantee the completeness, verifiability, anonymity, and uniqueness of the electronic voting scheme. The performance analysis shows that the computational efficiency of the proposed scheme is improved by about 66.7% compared with the Fan et al. scheme (https://doi.org/10.1016/j.future.2019.10.016).

The efficacy of electroacupuncture in among early diabetic patients with lower limb arteriosclerotic wounds.

Diabetic foot ulcers are the prevalent complication of diabetes mellitus, frequently culminating in arteriosclerosis of the lower extremities and consequent development of chronic wounds. The effectiveness of electroacupuncture (EA) as therapeutic intervention for promoting wound healing in this particular group of patients has been comprehensively assessed in this study. A randomized controlled trial involving 380 early diabetic patients with arteriosclerotic lesions of the lower limbs was conducted. Standard wound care plus EA was administered to the treatment group, while standard wound care alone was administered to the control group. The principal outcome assessed was the reduction in lesion size following the 8-week treatment period. Pain scores, recuperation time, and quality of life (QoL) evaluations constituted secondary outcomes. In comparison to the control group, the treatment group exhibited a significantly greater reduction in wound size (p < 0.05). The treatment group exhibited significantly reduced pain scores and significantly higher QoL scores (p < 0.05). The duration of recovery did not vary substantially among the groups (p > 0.05). Electroacupuncture thus appeared to be an effective adjunctive treatment for early diabetic patients with lower limb arteriosclerotic lesions, promoting pain relief and quality of life. Additional investigation is necessary to validate these results and delve into the underlying mechanisms of action.

Rafting and redissolution of γ' phase in Ni-Al alloy under external stress.

The volume fraction and rafting degree of the γ'-Ni3Al phase under stress and high temperature are the key characteristics of mechanical properties in Ni-based superalloys, the rafting and redissolution of γ' phase caused by the creep at high temperature damage the morphology and properties of Ni-based superalloys. The phase-field simulation is performed to study the rafting accompany with the redissolution of γ' phase under high temperature and loading stress in Ni-Al alloy, the driving force and kinetics evolution of the γ' rafting were revealed. During the rafting under continuous heating, the elastic energy in the vertical γ channel is different to that of the horizontal γ channel, this difference in elastic energy drives the elements diffusion directionally to form the γ' rafts morphology. With the increased tensile stress, the decrease of specific surface of the γ' phase slows down the redissolution, a higher volume fraction is reserved for the rafted γ' phase. With temperature increases, the interface of γ/γ' phase becomes more diffusional and wider under stress. The results give an insight on the rafting mechanism of γ' phase and the kinetics evolution in Ni-based superalloys under excess temperature.

Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches.

Non-small cell lung cancer (NSCLC) is often driven by mutations in the epidermal growth factor receptor (EGFR) gene. However, rare mutations such as G719X and S768I lack standard anti-EGFR targeted therapies. Understanding the structural differences between wild-type EGFR and these rare mutants is crucial for developing EGFR-targeted drugs. We performed a systematic analysis using molecular dynamics simulations, essential dynamics (ED), molecular mechanics Poisson-Boltzmann surface area, and free energy calculation methods to compare the kinetic properties, molecular motion, and free energy distribution between wild-type EGFR and the rare mutants' structures G719X-EGFR, S768I-EGFR, and G719X + S768I-EGFR. Our results showed that S768I-EGFR and G719X + S768I-EGFR have higher global and local conformational flexibility and lower thermal and global structural stability than WT-EGFR. ED analysis revealed different molecular motion patterns between S768I-EGFR, G719X + S768I-EGFR, and WT-EGFR. The A-loop and αC-helix, crucial structural elements related to the active state, showed a tendency toward active state development, providing a molecular mechanism explanation for NSCLC caused by EGFR S768I and EGFR G719C + S768I mutations. The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.

Inhibition of Hypoxia-Inducible Transcription Factor (HIF-1α) Signaling with Sulfonyl-γ-AApeptide Helices.

The development of inhibitors that selectively block protein-protein interactions (PPIs) is crucial for chemical biology, medicinal chemistry, and biomedical sciences. Herein, we reported the design, synthesis, and investigation of sulfonyl-γ-AApeptide as an alternative strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible factor 1α (HIF-1α) and p300 PPI by mimicking the helical domain of HIF-1α involved in the binding to p300. The designed molecules recognized the p300 protein with high affinity and potently inhibited the hypoxia-inducible signaling pathway. Gene expression profiling supported the idea that the lead molecules selectively inhibited hypoxia-inducible genes involved in the signaling cascade. Our studies also demonstrated that both helical faces consisting of either chiral side chains or achiral sulfonyl side chains of sulfonyl-γ-AApeptides could be adopted for mimicry of the α-helix engaging in PPIs. Furthermore, these sulfonyl-γ-AApeptides were cell-permeable and exhibited favorable stability and pharmacokinetic profiles. Our results could inspire the design of helical sulfonyl-γ-AApeptides as a general strategy to mimic the protein helical domain and modulate many other PPIs.

Characterization of a GH10 extremely thermophilic xylanase from the metagenome of hot spring for prebiotic production.

A xylanase gene (named xyngmqa) was identified from the metagenomic data of the Gumingquan hot spring (92.5 °C, pH 9.2) in Tengchong City, Yunnan Province, southwest China. It showed the highest amino acid sequence identity (82.70%) to endo-1,4-beta-xylanase from Thermotoga caldifontis. A constitutive expression plasmid (denominated pSHY211) and double-layer plate (DLP) method were constructed for cloning, expression, and identification of the XynGMQA gene. The XynGMQA gene was synthesized and successfully expressed in Escherichia coli DH5α. XynGMQA exhibited optimal activity at 90 °C and pH 4.6, being thermostable by maintaining 100% of its activity after 2 h incubated at 80 °C. Interestingly, its enzyme activity was enhanced by high temperatures (70 and 80 °C) and low pH (3.0-6.0). About 150% enzyme activity was detected after incubation at 70 °C for 20 to 60 min or 80 °C for 10 to 40 min, and more than 140% enzyme activity after incubation at pH 3.0 to 6.0 for 12 h. Hydrolytic products of beechwood xylan with XynGMQA were xylooligosaccharides, including xylobiose (X2), xylotriose (X3), and xylotetraose (X4). These properties suggest that XynGMQA as an extremely thermophilic xylanase, may be exploited for biofuel and prebiotic production from lignocellulosic biomass.

Unnatural helical peptidic foldamers as protein segment mimics.

Unnatural helical peptidic foldamers have attracted considerable attention owing to their unique folding behaviours, diverse artificial protein binding mechanisms, and promising applications in chemical, biological, medical, and material fields. Unlike the conventional α-helix consisting of molecular entities of native α-amino acids, unnatural helical peptidic foldamers are generally comprised of well-defined backbone conformers with unique and unnatural structural parameters. Their folded structures usually arise from unnatural amino acids such as N-substituted glycine, N-substituted-ß-alanine, ß-amino acid, urea, thiourea, α-aminoxy acid, α-aminoisobutyric acid, aza-amino acid, aromatic amide, γ-amino acid, as well as sulfono-γ-AA amino acid. They can exhibit intriguing and predictable three-dimensional helical structures, generally featuring superior resistance to proteolytic degradation, enhanced bioavailability, and improved chemodiversity, and are promising in mimicking helical segments of various proteins. Although it is impossible to include every piece of research work, we attempt to highlight the research progress in the past 10 years in exploring unnatural peptidic foldamers as protein helical segment mimics, by giving some representative examples and discussing the current challenges and future perspectives. We expect that this review will help elucidate the principles of structural design and applications of existing unnatural helical peptidic foldamers in protein segment mimicry, thereby attracting more researchers to explore and generate novel unnatural peptidic foldamers with unique structural and functional properties, leading to more unprecedented and practical applications.

α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo.

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

Complementary roles of EP2 and EP4 receptors in malignant glioma.

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE2 -initiated cAMP signalling via EP2 and EP4 receptors is involved in the tumourigenesis of multiple cancer types. However, whether or how EP2 and EP4 receptors contribute to GBM growth largely remains elusive. EXPERIMENTAL APPROACH: We performed comprehensive data analysis of gene expression in human GBM samples and determined their expression correlations through multiple bioinformatics approaches. A time-resolved fluorescence energy transfer (TR-FRET) assay was utilized to characterize PGE2 -mediated cAMP signalling via EP2 and EP4 receptors in human glioblastoma cells. Using recently reported potent and selective small-molecule antagonists, we determined the effects of inhibition of EP2 and EP4 receptors on GBM growth in subcutaneous and intracranial tumour models. KEY RESULTS: The expression of both EP2 and EP4 receptors was upregulated and highly correlated with a variety of tumour-promoting cytokines, chemokines, and growth factors in human gliomas. Further, they were heterogeneously expressed in human GBM cells, where they compensated for each other to mediate PGE2 -initiated cAMP signalling and to promote colony formation, cell invasion and migration. Inhibition of EP2 and EP4 receptors revealed that these receptors might mediate GBM growth, angiogenesis, and immune evasion in a compensatory manner. CONCLUSION AND IMPLICATIONS: The compensatory roles of EP2 and EP4 receptors in GBM development and growth suggest that concurrently targeting these two PGE2 receptors might represent a more effective strategy than inhibiting either alone for GBM treatment.

Effect of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with levodopa-induced dyskinesias.

This study aims to study the effffects of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with Levodopa-induced Dyskinesias (LIDs). In this experimental study, Levodopa-induced Dyskinesia (LID) rat models were established by 6-OHDA double-target injection and randomly assigned to six groups, with ten rats in each group. The rats were subjected to difffferent interventions for 28 days, and their behavior was observed. Additionally, the content of ΔFosB, a marker of neuronal activation, in the rat striatum was detected by immunohistochemistry and qRT-PCR. In contrallateral rotation behavior experiment and AIM experiment, the score of the model group was significantly increased, compared with the model group, the score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group was significantly decreased (P < 0.01), the score of the Western medicine group and the Tiaoshen Changzhi group was significantly lower than the ordinary acupuncture group (P < 0.01), there was no statistical significance between the Western medicine group and the Tiaoshen Changzhi group (P>0.05). In the left forelimb function test, the score of the model group was significantly decreased, and compared with the model group, the left forelimb function score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group were significantly increased (P < 0.01). The left forelimb function score of the Western medicine group and the Tiaoshen Changzhi group was higher than the ordinary acupuncture group (P < 0.05, P < 0.01). There was no statistical significance between Western medicine group and Tiaoshen Changzhi group (P > 0.05). After treatment, the content of ΔFosB in the striatum of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi acupuncture group all decreased, the Western medicine group was better than the ordinary acupuncture group (P < 0.01), and the Tiaoshen Changzhi acupuncture group was better than the ordinary acupuncture group (P < 0.05). Tiaoshen Changzhi acupuncture can improve the behavioral performance of LID rats, reduce abnormal involuntary movement and contralateral rotation behavior and enhance the motor function of the left forelimb of rats. One of its therapeutic mechanisms for LID may be to reduce the expression level of ΔFosB in the striatum of LID rats, thereby reducing the symptoms of LID rats.

Study on molecular mechanisms of CD4 dependency and independency of HIV-1 gp120.

Different HIV-1 strains have different antibody neutralization phenotypes (or CD4-dependencies). However, the molecular mechanisms underlying these differences remain to be elucidated. In this study, we constructed gp120 structural models from the CD4-dependent, neutralization-resistant JR-FL strain and the CD4-independent, neutralization-sensitive R2 strain and carried out several conventional molecular dynamics (MD) simulations and free energy landscape (FEL) constructions. Comparative analyses of the MD simulations and FELs indicated that R2 gp120 had higher global structural flexibility and greater conformational diversity than JR-FL gp120. This provides the preconditions for R2 gp120 to adopt a more open conformation than JR-FL gp120. Essential dynamics (ED) analysis showed that the collective motions of R2 gp120 tend towards an open state while those of JR-FL gp120 tend to retain a closed state. Based on conformational selection theory, R2 gp120's more readily sampled open state makes it more sensitive to neutralizing antibodies (or more CD4-independent) than JR-FL gp120, which may explain why the HIV-1 R2 and JR-FL strains show CD4-independent and -dependent phenotypes, respectively. Our study provides thermodynamic and kinetic insights into the CD4-dependent and -independent molecular mechanisms of HIV-1 gp120 and helps shed light on HIV-1 immune evasion.

Elastic Strain Relaxation of Phase Boundary of α' Nanoscale Phase Mediated via the Point Defects Loop under Normal Strain.

Irradiation-induced point defects and applied stress affect the concentration distribution and morphology evolution of the nanophase in Fe-Cr based alloys; the aggregation of point defects and the nanoscale precipitates can intensify the hardness and embrittlement of the alloy. The influence of normal strain on the coevolution of point defects and the Cr-enriched α' nanophase are studied in Fe-35 at.% Cr alloy by utilizing the multi-phase-field simulation. The clustering of point defects and the splitting of nanoscale particles are clearly presented under normal strain. The defects loop formed at the α/α' phase interface relaxes the coherent strain between the α/α' phases, reducing the elongation of the Cr-enriched α' phase under the normal strains. Furthermore, the point defects enhance the concentration clustering of the α' phase, and this is more obvious under the compressive strain at high temperature. The larger normal strain can induce the splitting of an α' nanoparticle with the nonequilibrium concentration in the early precipitation stage. The clustering and migration of point defects provide the diffusion channels of Cr atoms to accelerate the phase separation. The interaction of point defect with the solution atom clusters under normal strain provides an atomic scale view on the microstructure evolution under external stress.

Characterization of a thermophilic and glucose-tolerant GH1 ß-glucosidase from hot springs and its prospective application in corn stover degradation.

Introduction: ß-Glucosidase serves as the pivotal rate-limiting enzyme in the cellulose degradation process, facilitating the hydrolysis of cellobiose and cellooligosaccharides into glucose. However, the widespread application of numerous ß-glucosidases is hindered by their limited thermostability and low glucose tolerance, particularly in elevated-temperature and high-glucose environments. Methods: This study presents an analysis of a ß-glucosidase gene belonging to the GH1 family, denoted lqbg8, which was isolated from the metagenomic repository of Hehua hot spring located in Tengchong, China. Subsequently, the gene was cloned and heterologously expressed in Escherichia coli BL21(DE3). Post expression, the recombinant ß-glucosidase (LQBG8) underwent purification through a Ni affinity chromatography column, thereby enabling the in-depth exploration of its enzymatic properties. Results: LQBG8 had an optimal temperature of 70°C and an optimum pH of 5.6. LQBG8 retained 100 and 70% of its maximum activity after 2-h incubation periods at 65°C and 70°C, respectively. Moreover, even following exposure to pH ranges of 3.0-10.0 for 24 h, LQBG8 retained approximately 80% of its initial activity. Notably, the enzymatic prowess of LQBG8 remained substantial at glucose concentrations of up to 3 M, with a retention of over 60% relative activity. The kinetic parameters of LQBG8 were characterized using cellobiose as substrate, with Km and Vmax values of 28 ± 1.9 mg/mL and 55 ± 3.2 µmol/min/mg, respectively. Furthermore, the introduction of LQBG8 (at a concentration of 0.03 mg/mL) into a conventional cellulase reaction system led to an impressive 43.7% augmentation in glucose yield from corn stover over a 24-h period. Molecular dynamics simulations offered valuable insights into LQBG8's thermophilic nature, attributing its robust stability to reduced fluctuations, conformational changes, and heightened structural rigidity in comparison to mesophilic ß-glucosidases. Discussion: In summation, its thermophilic, thermostable, and glucose-tolerant attributes, render LQBG8 ripe for potential applications across diverse domains encompassing food, feed, and the production of lignocellulosic ethanol.

Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants.

To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.

Hierarchical medical system and local medical performance: A quasi-natural experiment evaluation in Shanghai, China.

Background: In order to maintain high standards of healthcare, it is necessary for medical departments to provide high-quality and affordable medical services to local residents. This has been widely accepted in developed countries, while the medical treatment systems in developing countries remain to be improved. This research is based on a pilot of a hierarchical medical system in Shanghai, China, to evaluate the effects on policy of medical reform in developing countries. Methods and results: By means of the difference-in-differences (DID) method, the causal relationship between medical care services' improvement and hierarchical medical systems' implementation could be identified. This project also explores the differential effects of policy intervention and confirms that the pilot showed a significant improvement in medical performance in central districts while the result remains uncertain in terms of suburban districts. Furthermore, the dynamic effect of a hierarchical medical system has also been identified with the event study method, while the policy pilot only had short-term effects on local medical resources' improvement. In order to ascertain the function mechanisms of hierarchical medical systems and explain why the policy pilot only had short-term effects, this project also conducts influencing mechanism analysis with the triple-differences method (also known as difference-in-difference-in-differences or DDD method). According to the empirical results, there is no direct evidence indicating the hierarchical medical system could bring obvious benefits from the perspectives of patients and medical institutions. Conclusions: For better implementation of hierarchical medical systems in the future, long-term supervision mechanisms should be given more attention in the enforcement process of hierarchical medical systems. At the same time, more safeguarding measures should be implemented, such as supervising the payment systems of the medical institution and conducting performance evaluation.

Rational design of a sensitivity-enhanced tracer for discovering efficient APC-Asef inhibitors.

The adenomatous polyposis coli (APC)-Rho guanine nucleotide exchange factor 4 (Asef) protein-protein interaction (PPI) is essential for colorectal cancer metastasis, making it a promising drug target. Herein, we obtain a sensitivity-enhanced tracer (tracer 7) with a high binding affinity (Kd = 0.078 µM) and wide signal dynamic range (span = 251 mp). By using tracer 7 in fluorescence-polarization assays for APC-Asef inhibitor screening, we discover a best-in-class inhibitor, MAI-516, with an IC50 of 0.041 ± 0.004 µM and a conjugated transcriptional transactivating sequence for generating cell-permeable MAIT-516. MAIT-516 inhibits CRC cell migration by specifically hindering the APC-Asef PPI. Furthermore, MAIT-516 exhibits no cytotoxic effects on normal intestinal epithelial cell and colorectal cancer cell growth. Overall, we develop a sensitivity-enhanced tracer for fluorescence polarization assays, which is used for the precise quantification of high-activity APC-Asef inhibitors, thereby providing insight into PPI drug development.

Helical sulfono-γ-AApeptides with predictable functions in protein recognition.

Sulfono-γ-AApeptides are a subset of possible sequence-specific foldamers that might be considered for the design of biomimetic drug molecular structures. Although they have been studied for a relatively short period of time, a number of structures and functions have been designed or discovered within this class of unnatural peptides. Examples of utilizing these sulfono-γ-AApeptides have demonstrated the potential that sulfono-γ-AApeptides can offer, however, to date, their application in biomedical sciences yet remains unexplored. This review mainly summarizes the helical folding conformations of sulfono-γ-AApeptides and their biological application as helical mimetics in medicinally relevant protein-protein interactions (PPIs) and assesses their potential for the mimicry of other α-helices for protein recognition in the future.