Tough double network hydrogels with rapid self-reinforcement and low hysteresis based on highly entangled networks.

Most tough hydrogels are reinforced by introducing energy dissipation mechanisms, but simultaneously realizing a high toughness and low hysteresis is challenging because the energy dissipation structure cannot recover rapidly. In this work, high mechanical performance highly entangled double network hydrogels without energy dissipation structure are fabricated, in which physical entanglements act as the primary effective crosslinking in the first network. This sliding entanglement structure allows the hydrogel network to form a highly uniform oriented structure during stretching, resulting in a high tensile strength of ~3 MPa, a fracture energy of 8340 J m-2 and a strain-stiffening capability of 47.5 in 90% water content. Moreover, almost 100% reversibility is obtained in this hydrogel via energy storage based on entropy loss. The highly entangled double network structure not only overcomes the typical trade-off between the high toughness and low hysteresis of hydrogels, but more importantly, it provides an insight into the application of entanglement structures in high-performance hydrogels.

SARS-CoV-2 evolution from the BA.2.86 to JN.1 variants: unexpected consequences.

SARS-CoV-2 is continuously evolving. The Omicron subvariant BA.2.86, with >30 mutations in its spike (S) protein compared with its predecessor strain BA.2, was expected to quickly become predominant worldwide, but this has not happened. Instead, its descendant strain, JN.1, with just one additional mutation, has become the predominant SARS-CoV-2 subvariant. Here, we offer a possible explanation for these unexpected consequences.

Acetolactate Decarboxylase as an Important Regulator of Intracellular Acidification, Morphological Features, and Antagonism Properties in the Probiotic Lactobacillus reuteri.

SCORE: This study identifies the coding gene (aldB) of acetolactate decarboxylase (ALDC) as an important regulatory gene of the intracellular pH in Lactobacillus reuteri (L. reuteri), uncovering the important role of ALDC in regulating intracellular pH, morphological features, and antagonism properties in the probiotic organism L. reuteri. METHODS AND RESULTS: The aldB mutant (ΔaldB) of L. reuteri is established using the homologous recombination method. Compare to the wild-type (WT) strain, the ΔaldB strain shows a smaller body size, grows more slowly, and contains more acid in the cell cytoplasm. The survival rate of the ΔaldB strain is much lower in low pH and simulated gastric fluid (SGF) than that of the WT strain, but higher in simulated intestinal fluid (SIF). The antagonism test demonstrates the ΔaldB strain can inhibit Listeria monocytogenes (L. monocytogenes) and Salmonella more effectively than the WT strain. Additionally, there is a dramatic decrease in the adhesion rate of Salmonella to Caco-2 and HT-29 cells in the presence of the ΔaldB strain compared to the WT strain. Simultaneously analyze, the auto-aggregation, co-aggregation, cell surface hydrophobicity (CSH), hemolytic, temperature, NaCl, oxidative stress, and antibiotic susceptibility of the ΔaldB strain are consistent with the features of probiotics. CONCLUSION: This study highlights that the aldB gene plays a significant role in the growth and antibacterial properties of L. reuteri.

Immunotherapy rechallenge of advanced lung adenocarcinoma with cadonilimab (PD-1/CTLA-4 Bi-specific antibody): a case report.

Lung adenocarcinoma (ADC) is a common pulmonary malignant disease with poor prognosis. Immunotherapeutic strategies are the current cornerstone of first-line therapy in driver-negative advanced lung ADC, but there is no treatment standard once the disease has progressed after the first-line application of immune checkpoint inhibitors (ICIs). Clinically, immunotherapy rechallenges are being attempted. However, it is undeniable that there are still great limitations to rechallenging patients with single- or double-ICI immunotherapy though immunotherapy rechallenges can bring new benefits. Cadonilimab (AK104), a unique bi-specific antibody targeting PD-1/CTLA-4, has similar biological activity but lower toxicity than the combination of CTLA-4 and PD-1 antibodies. Herein, we report a case of advanced lung ADC rechallenged with cadonilimab as a posterior-line therapy. The condition of the patient was maintained at stable disease for 6 months. This might provide a new idea and choice for the challenge of immunotherapy resistance.

Natural isoflavone glabridin targets PI3Kγ as an adjuvant to increase the sensitivity of MDA-MB-231 to tamoxifen and DU145 to paclitaxel.

Glabridin is a natural isoflavone with estrogen receptor agonism and significant anti-tumor activity. Additionally, glabridin has a regulation effect on PI3K/AKT/mTOR pathway, but its exact target remains unclear. In this study, we evaluated the antitumor activity of glabridin against breast cancer and prostate cancer cells, and further clarified its targeting to PI3K. We found that glabridin could significantly inhibit the cell viability of human breast cancer and prostate cancer cell lines. It induced caspase activation cascade and cell apoptosis through decreasing the mitochondrial transmembrane potential and increasing the intracellular reactive oxygen species (ROS). Moreover, glabridin could attenuate epithelial-mesenchymal transition (EMT) progression by inhibiting cell migration. PharmMapper calculation showed that PI3Kγ might be the most potential target protein because of the highest Normal Fit score (0.9735) and z'-score (0.9797). Molecular docking and bio-layer interferometry (BLI) analysis further demonstrated the PI3Kγ targeting of glabridin. In vivo experiments showed that glabridin can effectively inhibit the tumor growth of breast cancer xenograft model, and does not show obvious hepatorenal toxicity. Moreover, glabridin could effectively promote the anti-proliferation and pro-apoptotic effects of tamoxifen on MDA-MB-231 cell and taxol on DU145 cell. Elucidating the targeting of glabridin to PI3K may lay a theoretical foundation for the structural derivatization of glabridin, which is expected to greatly promote the application and development of glabridin in the field of cancer therapy.

Universal adhesion using mussel foot protein inspired hydrogel with dynamic interpenetration for topological entanglement.

Achieving adhesion of hydrogels to universal materials with desirable strength remains a challenge despite emerging application of hydrogels. Herein we present a mussel foot protein (Mfp) inspired polyelectrolyte hydrogel of poly(ethylenimine)/poly(acrylic acid)-dopamine (PEI/PAADA) developed for universal tough adhesion. The highly-concentrated electrostatic and hydrogen-bonding interactions in PEI/PAADA hydrogel resulted in a tensile strength, strain at break, and toughness of 0.297 MPa, 2784 % and 5.440 MJ m-3, respectively. Moreover, the hydrogel can heal itself from physical damages, even can be recycled after totally dried via rehydration because of the high flexibility and reversibility of its dynamic bonds. Combining the strategies of topological stitching and direct bonding, Mfp-derived catechol and PEI/PAA backbone in PEI/PAADA corporately facilitated robust adhesion of universal materials with shear strength of up to 4.4 MPa and peeling strength of 870 J m-2, which is over 10 times greater than that of commercial fibrin gel. The adhesive also exhibited self-healing capability for at least 5 cycles, good stability in 1 M NaCl solution and characteristic debonding catalyzed by calcium. Moreover, in vitro cell behavior and in vivo wound healing assays suggested the potential of PEI/PAADA as wound dressing.

Overcoming the Dilemma of In Vivo Stable Adhesion and Sustained Degradation by the Molecular Design of Polyurethane Adhesives for Bone Fracture Repair.

Bone adhesive is a promising candidate to revolutionize the clinical treatment of bone repairs. However, several drawbacks have limited its further clinical application, such as unreliable wet adhesive performance leading to fixation failure and poor biodegradability inhibiting bone tissue growth. By incorporating catechol groups and disulfide bonds into polyurethane (PU) molecules, an injectable and porous PU adhesive is developed with both superior wet adhesion and biodegradability to facilitate the reduction and fixation of comminuted fractures and the subsequent regeneration of bone tissue. The bone adhesive can be cured within a reasonable time acceptable to a surgeon, and then the wet bone adhesive strength is near 1.30 MPa in 1 h. Finally, the wet adhesive strength to the cortical bone will achieve about 1.70 MPa, which is also five times more than nonresorbable poly(methyl methacrylate) bone cement. Besides, the cell culture experiments also indicate that the adhesives show excellent biocompatibility and osteogenic ability in vitro. Especially, it can degrade in vivo gradually and promote fracture healing in the rabbit iliac fracture model. These results demonstrate that this ingenious bone adhesive exhibits great potential in the treatment of comminuted fractures, providing fresh insights into the development of clinically applicable bone adhesives.

Elevated Thyroglobulin Antibody Level is Associated with Decreased Anti-Müllerian Hormone in Women of Reproductive Age.

Purpose: Women with Hashimoto's thyroiditis (HT) have an increased risk of ovarian insufficiency. However, whether thyroid antibodies affect the ovarian reserve remains controversial. The aim of this study was to explore the possible relationship between anti-Müllerian hormone (AMH) and thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels in women of reproductive age. Methods: A total of 483 women between 18 and 45 years old who had their TPOAb, TgAb, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and AMH levels measured on the same day were enrolled in this study. The levels of TSH, FT4, TPOAb, and TgAb, the prevalence of overt and subclinical hypothyroidism, and the positive rate of TPOAb and TgAb were compared between patients with low (below the 10th percentile), normal (10th to 90th percentile), and high (higher than the 90th percentile) AMH levels. Results: The median AMH level was 1.72 (0.33-4.27) ng/mL. A total of 9.9% of patients had low AMH levels. The TgAb levels and the prevalence of TgAb positivity were higher in the low AMH group (37.62 (13.10-232.68) IU/mL, 35.42%) than in the normal (12.46 (10.0-67.04) IU/mL, 19.59%) and high (13.61 (10.0-95.74) IU/mL, 23.4%) AMH groups (p=0.001, p=0.040, respectively). Serum AMH levels were inversely correlated with TgAb levels (r = -0.114, p=0.013). Conclusion: The AMH of women of reproductive age is affected by HT. Furthermore, women with the lowest AMH level had higher levels of TgAb and a positive rate of TgAb, and high TgAb levels may cause autoimmune damage to the ovaries.

Mechanically Reinforced and Injectable Universal Adhesive Based on a PEI-PAA/Alg Dual-Network Hydrogel Designed by Topological Entanglement and Catechol Chemistry.

Universal adhesion of hydrogels to diverse materials is essential to their extensive applications. Unfortunately, tough adhesion of wet surfaces remains an urgent challenge so far, requiring robust cohesion strength for effective stress dissipation. In this work, a dual-network hydrogel polyethylenimine-poly(acrylic acid)/alginate (PEI-PAA/Alg) with excellent mechanical strength is realized via PEI-PAA complex and calcium alginate coordination for universal adhesion by the synergistic effort of topological entanglement and catechol chemistry. The dual networks of PEI-PAA/Alg provide mechanically reinforced cohesion strength, which is sufficient for energy dissipation during adhesion with universal materials. After the integration of mussel-inspired dopamine into PAA or Alg, the adhesive demonstrates further improved adhesion performance with a solid adherend and capability to bond cancellous bones. Notably, the dopamine-modified adhesive exhibits better instant adhesion and reversibility with wet surfaces compared with commercial fibrin. Adhesion interfaces are investigated by SEM and micro-FTIR to verify the effectiveness of strategies of topological entanglement. Furthermore, the adhesive also possesses great injectability, stability, tissue adhesion, and biocompatibility. In vivo wound healing and histological analysis indicate that the hydrogel can promote wound closure, epidermis regeneration, and tissue refunctionalization, implying its potential application for bioadhesive and wound dressing.

Effects of Aromatherapy Massage Combined with TCM Emotional Release Technique on Maternal and Neonatal Physical and Mental Health and Family Relationship in Patients with Postpartum Depression.

Objective: To explore the effects of aromatherapy massage combined with TCM emotional release technique on maternal and neonatal physical and mental health and family relationships in patients with postpartum depression. Methods: A The total number of participants in the study was 160, who were evenly distributed through random assignment into four groups of 40 in each group. This random assignment process was designed to ensure that each group was similar in terms of demographic characteristics and other potential confounding factors to increase the comparability and internal validity of the study. The 160 patients with postpartum depression admitted to the obstetrics department of the Hebei 3a Hospital were enrolled between April 2021 and May 2022, and they were randomly divided into control group, sweet orange aromatherapy massage group, emotional release technique group and combination group, 40 cases in each group. The negative emotions, stress state, mania, levels of neurotransmitters and family intimacy adaptability were compared in the four groups before and after intervention. Results: After the intervention, scores of a generalized anxiety disorder (GAD-7) and Edinburgh Postpartum Depression Scale (EPDS) in the combination group were higher than those in the other three groups, and were higher in the emotional release technique group and sweet orange aromatherapy massage group than control group (P < .05). After the intervention, scores of PTSD Checklist-Civilian Version (PCL) and 32-item hypomania checklist (HCL-32) were the highest in the control group, followed by the sweet orange aromatherapy massage group, emotional release technique group and combination group (P < .05). After the intervention, levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) were the highest in the combination group, followed by the emotional release technique group, sweet orange aromatherapy massage group, and control group (P < .05), and adaptability level of family intimacy was also in the same order (P < .05). In the combined treatment group, generalized anxiety disorder score (GAD-7) and postpartum depression scale (EPDS) scores were increased compared with the control group, indicating increased symptom severity in these two areas. GAD-7 and EPDS scores also increased significantly in the emotional release technique group and the sweet orange aromatherapy massage group. Although the magnitude of the increase may be different, both interventions seemed to lead to an increase in anxiety and depressive symptoms. As the intervention progressed, the control group had the highest scores on the Post-Traumatic Stress Disorder Checklist-Citizen Version (PCL) and the Hyperactivity Checklist 32 (HCL-32), followed by the Sweet Orange Aromatherapy Massage Group and the Emotional Release Technique group and combined treatment group. This indicates that symptom severity was significantly higher in the control group than in the other intervention groups in both areas. Levels of serotonin (5-HT) and dopamine (DA) increased in different groups, the highest in the combined treatment group, followed by the emotional release technique group, sweet orange aromatherapy massage group and the control group. This may indicate that the combination treatment had a positive effect on modulating the levels of these neurotransmitters. The adaptation level of family intimacy also changed according to the same trend. The highest level was in the combined treatment group, followed by the emotional release technique group, the sweet orange aromatherapy massage group and the control group. This may mean that combined treatment has a positive impact on the adaptability of family relationships. Conclusion: Aromatherapy massage combined with an emotional release technique can reduce negative emotions, stress, and mania, improve positive emotions and family intimacy adaptability of patients. These findings have important clinical implications as they relate to the well-being of women and families in the postpartum period. Reducing negative emotions and stress will improve women's mental health and improve their quality of life. In addition, positive emotional support helps create a healthy family atmosphere and has a positive impact on society as a whole.

Effects of cadmium on liver function in turtle Mauremys reevesii.

This research was designed to investigate the effects of cadmium (Cd) on liver function in turtle Mauremys reevesii. Turtles were divided into 4 groups at random. The turtles were injected intraperitoneally with Cd at 0, 7.5, 15, 30 mg kg-1 Cd chloride separately. Liver index was calculated. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the content of TP in liver were examined with biochemical methods. The results indicated that the liver index of turtles changed obviously only at higher dose and longer time. The activities of ALT and AST in liver increased with prolongation of exposure time in a dose-dependent manner. TP content in liver was lower than that in the control. In summary, Cd had an obvious toxic effect on liver tissues of freshwater turtle Mauremys reevesii, and it was dose dependent with the extension of exposure time. But the results also showed that the turtle had strong tolerance to Cd.

Comparison of ruminal microbiota, metabolomics, and milk performance between Montbéliarde×Holstein and Holstein cattle.

Holstein cattle are well known for their high average milk yield but are more susceptible to disease and have lower fecundity than other breeds of cattle. The purpose of this study was to explore the relationship between ruminal metabolites and both milk performance and ruminal microbiota composition as a means of assessing the benefits of crossbreeding Montbéliarde and Holstein cattle. This experiment crossbred Holstein with Montbéliarde cattle, aimed to act as a reference for producing high-quality dairy products and improving the overall efficiency of dairy cattle breeding. Based on similar age, parity and lactation time, 46 cows were selected and divided into two groups (n = 23 per group) for comparison experiment and fed the same formula: Montbéliarde×Holstein (MH, DIM = 33.23 ± 5.61 d), Holstein (H, DIM = 29.27 ± 4.23 d). Dairy herd improvement (DHI) data is an important basis for evaluating the genetic quality of bulls, understanding the quality level of milk, and improving feeding management. We collected the DHI data of these cows in the early lactation, middle lactation and late lactation period of 10 months. The results showed that the average milk production and protein content in Montbéliarde×Holstein were 1.76 kg (34.41 kg to 32.65 kg, p > 0.05) and 0.1% (3.54 to 3.44%, p < 0.05) higher than in Holstein cattle. Moreover, milk from Montbéliarde×Holstein cattle had lesser somatic cell score (1.66 to 2.02) than Holstein cattle (p < 0.01). A total of 10 experimental cattle in early lactation were randomly selected in the two groups (Lactation time = 92.70 ± 6.81), and ruminal fluid were collected by oral gastric tube. Using 16S rRNA microbial sequencing, we compared the ruminal microbiota composition and found that Montbéliarde×Holstein cattle had a lower abundance of Alphaproteobacteria (p < 0.05) and higher abundance of Selenomonas than Holstein cattle (p < 0.05). These bacteria play roles in protein degradation, nitrogen fixation and lactic acid degradation. The abundance of Succiniclasticum was also greater in Montbéliarde×Holstein cattle (p = 0.053). Through ruminal metabolome analysis, we found that the levels of trans-ferulic acid, pyrrole-2-carboxylic acid, and quinaldic acid were significantly increased in Montbéliarde×Holstein cattle, while that of lathosterol was significantly decreased. The changes in the levels of these metabolites could confer improved antioxidant, anti-inflammatory, and antibacterial activities.

An engineered recombinant protein containing three structural domains in SARS-CoV-2 S2 protein has potential to act as a pan-human coronavirus entry inhibitor or vaccine antigen.

The threat to global health caused by three highly pathogenic human coronaviruses (HCoV), SARS-CoV-2, MERS-CoV and SARS-CoV, calls for the development of pan-HCoV therapeutics and vaccines. This study reports the design and engineering of a recombinant protein designated HR1LS. It contains three linked molecules, each consisting of three structural domains, including a heptad repeat 1 (HR1), a central helix (CH), and a stem helix (SH) region, in the S2 subunit of SARS-CoV-2 spike (S) protein. It was found that HR1LS protein automatically formed a trimer able to bind with heptad repeat 2 (HR2) region in the SARS-CoV-2 S2 subunit, thus potently inhibiting HCoV fusion and entry into host cells. Furthermore, immunization of mice with HR1LS, when combined with CF501 adjuvant, resulted in the production of neutralizing antibodies against infection of SARS-CoV-2 and its variants, as well as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and MjHKU4r-CoV-1. These results suggest that HR1LS is a promising candidate for further development as a novel HR1-trimer-based pan-HCoV entry inhibitor or vaccine for the treatment and prevention of infection by SARS-CoV-2 and its variants, but also other HCoVs with the potential to cause future emerging and re-emerging infectious coronavirus diseases.

A 0D-2D Heterojunction Bismuth Molybdate-Anchored Multifunctional Hydrogel for Highly Efficient Eradication of Drug-Resistant Bacteria.

Due to the increasing antibiotic resistance and the lack of broad-spectrum antibiotics, there is an urgent requirement to develop fresh strategies to combat multidrug-resistant pathogens. Herein, defect-rich bismuth molybdate heterojunctions [zero-dimensional (0D) Bi4MoO9/two-dimensional (2D) Bi2MoO6, MBO] were designed for rapid capture of bacteria and synergistic photocatalytic sterilization. The as-prepared MBO was experimentally and theoretically demonstrated to possess defects, heterojunctions, and irradiation triple-enhanced photocatalytic activity for efficient generation of reactive oxygen species (ROS) due to the exposure of more active sites and separation of effective electron-hole pairs. Meanwhile, dopamine-modified MBO (pMBO) achieved a positively charged and rough surface, which conferred strong bacterial adhesion and physical penetration to the nanosheets, effectively trapping bacteria within the damage range and enhancing ROS damage. Based on this potent antibacterial ability of pMBO, a multifunctional hydrogel consisting of poly(vinyl alcohol) cross-linked tannic acid-coated cellulose nanocrystals (CPTB) and pMBO, namely CPTB@pMBO, is developed and convincingly effective against methicillin-resistant Staphylococcus aureus in a mouse skin infection model. In addition, the strategy of combining a failed beta-lactam antibiotic with CPTB@pMBO to photoinactivation with no resistance observed was developed, which presented an idea to address the issue of antibiotic resistance in bacteria and to explore facile anti-infection methods. In addition, CPTB@pMBO can reduce excessive proteolysis of tissue and inflammatory response by regulating the expression of genes and pro-inflammatory factors in vivo, holding great potential for the effective treatment of wound infections caused by drug-resistant bacteria.

Modified Podophyllotoxin Phenoxyacetamide Phenylacetate Derivatives: Tubulin/AKT1 Dual-Targeting and Potential Anticancer Agents for Human NSCLC.

Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 µM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 µM) and 300 times higher than gefitinib (IC50 = 32.15 µM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.

MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation.

MiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.

An HR2-Mimicking Sulfonyl-γ-AApeptide Is a Potent Pan-coronavirus Fusion Inhibitor with Strong Blood-Brain Barrier Permeability, Long Half-Life, and Promising Oral Bioavailability.

Neutralizing antibodies and fusion inhibitory peptides have the potential required to combat the global pandemic caused by SARS-CoV-2 and its variants. However, the lack of oral bioavailability and enzymatic susceptibility limited their application, necessitating the development of novel pan-CoV fusion inhibitors. Herein we report a series of helical peptidomimetics, d-sulfonyl-γ-AApeptides, which effectively mimic the key residues of heptad repeat 2 and interact with heptad repeat 1 in the SARS-CoV-2 S2 subunit, resulting in inhibiting SARS-CoV-2 spike protein-mediated fusion between virus and cell membranes. The leads also displayed broad-spectrum inhibitory activity against a panel of other human CoVs and showed strong potency in vitro and in vivo. Meanwhile, they also demonstrated complete resistance to proteolytic enzymes or human sera and exhibited extremely long half-life in vivo and highly promising oral bioavailability, delineating their potential as pan-CoV fusion inhibitors with the potential to combat SARS-CoV-2 and its variants.

An Artificial Peptide-Based Bifunctional HIV-1 Entry Inhibitor That Interferes with Viral Glycoprotein-41 Six-Helix Bundle Formation and Antagonizes CCR5 on the Host Cell Membrane.

Human immunodeficiency virus type 1 (HIV-1) is characterized by high variability and drug resistance. This has necessitated the development of antivirals with a new chemotype and therapy. We previously identified an artificial peptide with non-native protein sequence, AP3, with the potential to inhibit HIV-1 fusion through targeting hydrophobic grooves on the N-terminal heptad repeat trimer of viral glycoprotein gp41. Here, a small-molecule HIV-1 inhibitor targeting chemokine coreceptor CCR5 on the host cell was integrated into the AP3 peptide, producing a novel dual-target inhibitor with improved activity against multiple HIV-1 strains including those resistant to the currently used anti-HIV-1 drug enfuvirtide. Its superior antiviral potency in comparison with the respective pharmacophoric moieties is in consonance with the dual binding of viral gp41 and host factor CCR5. Therefore, our work provides a potent artificial peptide-based bifunctional HIV-1 entry inhibitor and highlights the multitarget-directed ligands approach in the development of novel therapeutic anti-HIV-1 agents.