The mechanisms of dimerization of α-synuclein from full-length monomers and their structural features have been investigated through molecular dynamics simulations in this study. The dimerization of α-syn plays a critical role in the fibrillogenesis mechanism and could initiate and trigger α-syn to aggregate by conformational transforming. According to the alignment between three regions of α-syn monomer, eight diverse starting structures have been constructed. However, only five configurations show the dimeric structures, and the detailed properties of three dimers of them are discussed. During the simulations, both identical α-syn peptides (P1 and P2) of these three dimers reduce the high contents of α-helix from their native folded structures, while the contents of β-sheet increase. Antiparallel β-hairpin motifs within the α-syn peptide are formed by intramolecular interactions. The β-hairpin regions are adjacent to the nonamyloid β component (NAC) of α-syn, and these structural features are consistent with the experimental observation. Moreover, intermolecular β-sheets also are generated between P1 and P2 through hydrogen bonding interactions. The dimers produce both intramolecular β-hairpin and intermolecular β-sheet characters; the former is presented in monomer and oligomer of α-syn, and the latter occurs in the fibril structure. The simulations also show several other interactions such as hydrophobic interactions and salt-bridges, which would contribute to making the α-syn dimers more stable with the aforementioned effects. The results may pave the way to design small molecules to inhibit the dimerization in order to block the aggregation of α-syn in the future.

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on “shock and kill” strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.Keywords: heat shock factor 1; histone acetylation; latent HIV; resveratrol; synergistic reactivation;

A facile and versatile “on-water” protocol for the synthesis of pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/H2O was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists.Keywords: anti-influenza virus; catalyst-free; green reaction and separation; one-water reaction; pyrazolo[3,4-b]pyridinone;

•Oligothiophene compounds are novel skeletons that inhibit influenza virus.•Compound 3sf is the most active inhibitor with an IC50 of 0.029 μM.•Docking study shows that compound 3sf binds to the cavity of H5N1 HA2 stem region.Hemagglutinin (HA) which is essential for influenza viral infection and replication has become a target for the design of anti-influenza drugs. A novel series of oligothiophene compounds focused on the target were synthesized as specific inhibitors against the H5 subtype of influenza A viruses because oligothiophene has stronger π–π interactions with residues F1102 and M241 of HA2 side chains. Oligothiophene compounds were designed and synthesized by a series of alkylation, azidation, amination and amidation reactions. The entry inhibitory activities of those compounds were tested at a cellular level against H5N1 influenza pseudovirus. Compound 3sf was revealed as the most active inhibitor in this series with an IC50 of 0.029 μM. The activity of 3sf is almost 1000 times that of the positive reference compound (CL-385319). A structure-activity analysis of these compounds demonstrated that the size of the oligothiophene compounds was very important for the inhibitory activity. Four compounds (3sk, 3sf, 3sc and 4sc) of strong inhibitiory activity against H5N1 influenza pseudovirus were assessed against H1N1 influenza virus MDCK. They also showed strong inhibitiory activity with IC50s of 3.292 μM, 1.240 μM, 1.119 μM and 0.768 μM, respectively.3sf against H5N1 influenza pseudovirus with an IC50 of 0.029 μM, against H1N1 influenza virus MDCK with an IC50 of 1.240 μM.Download high-res image (258KB)Download full-size image

Identification of the host or viral factors that enhance HIV infection is critical for preventing sexual transmission of HIV. Amyloid fibrils derived from human semen, including semen-derived enhancer of virus infection and semenogelins, enhance HIV-1 infection dramatically in vitro. In this study, we reported that a short-degraded peptide fragment 1 (DPF1) derived from native HIV-1 envelope protein gp120-loaded rat hepatocytes, formed fibrils by self-assembly and thus enhanced HIV-1 infection by promoting the binding of HIV-1 to target cells. Furthermore, DPF1-formed fibrils might be used as a crossing seed to accelerate the formation of semen-derived enhancer of virus infection and semenogelin fibrils. It will be helpful to clarify the viral factors that affect HIV-1 infection. DPF1 as an analog of gp120 containing the critical residues for CD4 binding might be useful for designing of HIV vaccines and developing HIV entry inhibitors.

Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the GreysWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.

Bone lytic diseases including osteoporosis, rheumatoid arthritis, and bone metastatic tumors affect hundreds of millions people worldwide. Targeting over-activated osteoclasts as an anti-resorptive treatment becomes an important strategy to treat osteolytic diseases. Artesunate is a compound derived from artemisinin (qinghaosu) and has been used to treat malaria and rheumatoid arthritis clinically in China, but its role in osteolysis is unknown. Here, we found that artesunate could suppress RANKL-induced osteoclastogenesis and bone resorption from 1.56 to 12.5 μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50 μM, but had no effects on RANKL-induced NF-κB activation (NF-κB luciferase activity, IκB-α degradation and nuclear NF-κB p65 protein level) from 3.125 to 12.5 μM in pre-osteoclastic RAW264.7 cells. Interestingly, artesunate could significantly inhibit RANKL-induced NFATc1 activation measured by NFAT luciferase activity, NFATc1 mRNA and nuclear NFATc1 protein levels from 3.125 to 12.5 μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5 μM. In addition, the NFATc1 targeted osteoclast-specific genes expression including cathepsin K, MMP-9, and TRAP was reduced by artesunate. Finally, we showed that artesunate was able to reverse the bone loss in an ovariectomized mouse model in vivo accompanied with reduced RANKL, RANKL/OPG, and TRAP-5b levels. This study indicates that artesunate inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting PLCγ1-Ca2+-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease.Download high-res image (81KB)Download full-size image

Influenza viruses, the main cause of respiratory tract diseases, cause high morbidity and mortality in humans. Excessive inflammation in the lungs is proposed to be a hallmark for the severe influenza virus infection, especially influenza A virus infection. Strategies against inflammation induced by influenza A virus infection could be a potential anti-influenza therapy. Here, lethal dose of mouse-adapted H1N1 strain PR8A/PR/8/34 was inoculated C57BL/6 mice to detect the anti-influenza activity of andrographolide, the active component of traditional Chinese medicinal herb Andrographis paniculata, with or without influenza virus entry inhibitor CL-385319. Treatment was initiated on 4 days after infection. The survival rate, body weight, lung pathology, viral loads, cytokine expression were monitored in 14 days post inoculation. The combination group had the highest survival rate. Andrographolide treatment could increase the survival rate, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by infection. Mechanism studies showed the NF-κB and JAK-STAT signaling pathway were involved in the activity of andrographolide. In conclusion, combination of virus entry inhibitor with immunomodulator might be a promising therapeutic approach for influenza.

•A series of oleanane-type triterpenes were designed and synthesized.•These compounds as H5N1 entry inhibitors showed the potent inhibitory activity.•Intensive SARs studies were conducted.•Introduction of a disubstituted amide structure at the 17-COOH can improve the SI.•Alteration of the C-3 configuration of OA improves the selective index.A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry.A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitor, of which compound 8 showed the strongest inhibition activity with IC50 of 2.4 μM.

Hydrogels have been widely studied in various biomedical applications, such as tissue engineering, cell culture, immunotherapy and vaccines, and drug delivery. Peptide-based nanofibers represent a promising new strategy for current drug delivery approaches and cell carriers for tissue engineering. This review focuses on the recent advances in the use of self-assembling engineered β-sheet peptide assemblies for biomedical applications. The applications of peptide nanofibers in biomedical fields, such as drug delivery, tissue engineering, immunotherapy, and vaccines, are highlighted. The current challenges and future perspectives for self-assembling peptide nanofibers in biomedical applications are discussed.

Two new 2-benzylpyridin-4-one containing metabolites, aspernigrins C (3) and D (4), together with six known compounds (1, 2, and 5–8), were isolated from the marine-derived fungus Aspergillus niger SCSIO Jcsw6F30. The structures of the new compounds were determined by NMR, MS, and optical rotation analyses. All the isolated compounds were evaluated for their inhibitory activities against infection with HIV-1 SF162 in TZM-bl cells. Malformin C (5) showed the strongest anti-HIV-1 activity with IC50 of 1.4 ± 0.06 μM (selectivity index, 11.4), meanwhile aspernigrin C (3) also exhibited potent activity with IC50 of 4.7 ± 0.4 μM (selectivity index, 7.5).

Racemic C6-unsubstituted tetrahydropyrimidines (THPs) are a series of fluorophores with a strong aggregation-induced emission (AIE) effect. However, they do not possess the structural features of conventional AIE compounds. In order to understand their AIE mechanism, here, the influences of the molecular packing mode and the conformation on the optical properties of THPs were investigated using seven crystalline polymorphs of three THPs (1–3). The racemic THPs 1–3 have low-conjugated and highly flexible molecular structures, and hence show practically no emission in different organic solvents. However, the fluorescence quantum yields of their polymorphs are up to 93%, and the maximum excitation (λex) and emission (λem) wavelengths of the polymorphs are long at 409 and 484 nm, respectively. Single-crystal structures and theoretical calculation of the HOMOs and LUMOs based on the molecular conformations of these polymorphs indicate that the polymorphs with the shortest λex and λem values possess a RS-packing mode (R- and S-enantiomers self-assemble as paired anti-parallel lines) and a more twisted conformation without through-space conjugation between the dicarboxylates, but the polymorphs with longer λex and λem values adopt a RR/SS-packing mode (R- and S-enantiomers self-assemble as unpaired zigzag lines) and a less twisted conformation with through-space conjugation between the dicarboxylates. The molecular conformations of 1–3 in all these polymorphs are stereo and more twisted than those in solution. Although 1–3 are poorly conjugated, the radiative rate constants (kr) of their polymorphs are as large as conventional fluorophores (0.41–1.03 × 108 s−1) because of improved electronic conjugation by both through-bond and through-space interactions. Based on the obtained results, it can be deduced that the strong AIE arises not only from the restriction of intramolecular motion but also from enhanced electronic coupling and radiatively-favored inter-crossed local excitation (LE) and intramolecular charge transfer (ICT) excitation states. The abnormal molecular structures, easily-controllable self-assembly of the R- and S-enantiomers, and the strong AIE effect make THPs very useful fluorophores for applications and theoretical research.

•A series of pentacyclic triterpenes have been designed and synthesized.•These compounds as H5N1 entry inhibitors exhibited the potent inhibitory activity.•Intensive SARs studies were conducted.•Introduction of a disubstituted amide structure at the 17-COOH can improve the SI.•Alteration of the C-3 configuration of ursolic acid improves the selective index.A series of methyl ursolate 3-O-β-chacotrioside analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 3 previously discovered by us. Detailed structure–activity relationships (SARs) studies on the aglycone of compound 3 indicated that both the type of pentacyclic triterpene and the subtle modification of ursolic acid as an aglycon had key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of ursolic acid or alteration of the C-3 configuration of ursolic acid from 3β-to 3α-forms was helpful to significantly improve the selective index while keeping their antiviral activities.A series of pentacyclic triterpen were designed and synthesized in a practical way based on compound 3. Most compounds exhibited potent the inhibitory activity against the entry of H5N1 influenza virus.

A series of 3-O-β-chacotriosyl oleanane-type triterpenes have been designed, synthesized and evaluated as H5N1 entry inhibitors, based on a small molecule inhibitor, saponin 1, previously discovered by us. Detailed structure–activity relationship (SAR) studies on the aglycone of compound 1 indicated that oleanane-type triterpenes with conserved structural features as the aglycone favored the antiviral activity. The results suggested that the introduction of bulky groups onto the 28-COOH of OA was helpful for significantly improving the selectivity index while keeping the antiviral activities, which was opposite to what was found for the GA analogs. Compound 5 was selected for further mechanistic studies because of its distinguished inhibition activity and good selectivity index. Molecular simulation analysis confirmed that compound 5 stabilized the HA2 subunit of hemagglutinin (HA) by binding with amino acid residues THR-189, LYS-156, and ARG-133A, and therefore may prevent HA from undergoing conformational rearrangement, which is a critical step for viral entry.

Luteolin is a well-known flavonoid with various pharmacological properties but has low bioavailability due to glucuronidation. This study investigated the time-course of luteolin glucuronidation by 12 human UDP-glucuronosyltransferases (UGTs) and its intestinal first-pass metabolism in mice. Six metabolites, including two novel abundant diglucuronides [3′,7-O-diglucuronide (diG) and 4′,7-diG] and four known ones, were identified. UGT1A6 and UGT1A9 generated almost only monoglucuronides (G’s). The production of 3′,7-diG followed a sequential time-dependent process along with decrease of 3′-G mainly by UGT1A1, indicating that 3′,7-diG was produced from 3′-G. Metabolism in mice intestine differed from that in humans. Probenecid, a nonspecific UGT inhibitor, did not affect absorption but significantly inhibited production of 7-, 4′-, and 3′-G, and enhanced the formation of another novel metabolite, 5-G, in mice. In conclusion, diglucuronide formation is time-dependent and isoform-specific. UGT1A1 preferentially generates diG, whereas UGT1A6 and UGT1A9 share a preference for G production.

A sensitive and visible fluorescence-turn-on probe for the critical micelle concentration (CMC) determination of ionic surfactants has been developed based on practically no emission in micelles but strong aggregation-induced emission in solution of racemate tetrahydropyrimide THP-1. CMC values were determined via the inflexion with the strongest fluorescence intensity.

•A series of short arginine, lysine and tryptophan containing lipopeptides have been designed and synthesized.•Their antimicrobial activities were evaluated against Staphylococcus aureus, Escherichia coli, and Candida albicans.•The hemolytic effects of these peptides were tested.•The structure and activity relationships of these peptides were discussed.•Peptides C10-RKWWK showed a good antimicrobial activity, moderate cytotoxicity and multiple modes of action.Tryptophan and arginine rich antimicrobial peptides (AMPs) possess high potencies against both gram positive and gram negative bacteria, while lipopeptides represent another family of promising antimicrobial agents to combat invading pathogens. In the present study, we have synthesized a series of very short arginine, lysine and tryptophan containing lipopeptides and evaluated their antimicrobial activities against a panel of pathogenic microorganisms including Staphylococcus aureus, Escherichia coli, and Candida albicans. The results showed that most of these peptides were effective against tested strains with MIC values ranging from 3.9 to 62.5 μg/mL. In addition to the small size, potent bactericidal activity, low to moderate hemolytic toxicity and membrane disruption ability, several peptides such as C10-RIKWWK and C10-RKWWK apparently retarded the migration of DNA on agarose gel in the DNA-binding assay, which implied the multiple modes of action in their bacteria-killing mechanism. These peptides revealed a promising therapeutic potential to develop as new antimicrobial agents.A series of short lipopeptides have been synthesized and evaluated for their antimicrobial activity. C10-RKWWK and C10-RIKWWK showed the DNA-binding potential and membrane disruption ability in addition to the potent antimicrobial activities.

The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical–basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

Several dibenzocyclooctatetraene derivatives (5–7) and related biphenyls (8–11) were designed, synthesized, and evaluated for inhibition of cancer cell growth and the NF-κB signaling pathway. Compound 5a, a dibenzocyclooctatetraene succinimide, was discovered as a potent inhibitor of the NF-κB signaling pathway with significant antitumor activity against several human tumor cell lines (GI50 1.38–1.45 μM) and was more potent than paclitaxel against the drug-resistant KBvin cell line. Compound 5a also inhibited LPS-induced NF-κB activation in RAW264.7 cells with an IC50 value of 0.52 μM, prevented IκB-α degradation and p65 nuclear translocation, and suppressed LPS-induced NO production in a dose-dependent manner. The antitumor data in cellular assays indicated that relative positions and types of substituents on the dibenzocyclooctatetraene or acyclic biphenyl as well as torsional angles between the two phenyls are of primary importance to antitumor activity.

We previously reported the novel efficient proton/heat-promoted four-component reactions (4CRs) of but-2-ynedioates, two same/different primary amines, and aldehydes for the synthesis of tetra- and pentasubstituted polyfunctional dihydropyrroles. If aromatic and aliphatic amines were used as reagents, four different series of products should be obtained via the permutation and combination of aromatic and aliphatic primary amines. However, only three/two rather four different series of tetra-/pentasubstisuted dihydropyrroles could be prepared via the proton/heat-promoted 4CRs. Herein, Cu(OAc)2·H2O, a Lewis acid being stable in air and water, was found to be an efficient catalyst for the 4CR synthesis of all the four different series of tetra-/pentasubstisuted dihydropyrroles. The copper-catalyzed 4CR could produce target products at room temperature in good to excellent yields. Interestingly, benzaldehyde, in addition to being used as a useful reactant for the synthesis of pentasubstituted dihydropyrroles, was found to be an excellent additive for preventing the oxidation of aromatic amines with copper(II) and ensuring the sooth conduct of the 4CRs for the synthesis of tetrasubstituted dihydropyrroles with aryl R3. In addition, salicylic acid was found to be needed to increase the activities and yields of the copper-catalyzed 4CRs for the synthesis of petasubstituted diyhydropyrroles. On the basis of experimental results, the enamination/amidation/intramolecular cyclization mechanism was proposed and amidation is expected to be the rate-limited step in the copper-catalyzed 4CRs.Keywords: copper catalysis; dihydropyrroles; multicomponent reactions; nitrogen heterocycles; one-pot reaction; synthetic methods

Fluorescence enhancement and particle-size control of organic fluorophores are of general interest owing to their wide applications. We recently developed a convenient five-component reaction (5CR) for the synthesis of a novel class of racemates, C-6 unsubstituted tetrahydropyrimidines with strong aggregation-induced emission (AIE) properties. The copper-induced fluorescence enhancement and particle-size decrease of the racemate dimethyl 2-(4-hydroxy-3-methoxyphenyl)-1,3-diphenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (THP-1), one of the 5CR products, were investigated in this paper. THP-1 shows useful AIE properties, which have attracted great attention recently, and the unusual size-independent emission (SIE) properties reported in our previous work. The fluorescence intensity of THP-1 increased upon adding Cu2+ and a good linear relationship between the fluorescence intensity at the peak position and the Cu2+ concentration was observed in the range of 0–80 μM of Cu2+. The fluorescence response to Cu2+ is highly selective over other common transition metal ions. Most importantly, the suspension particle sizes of THP-1 were found to gradually decrease upon adding Cu2+. This method for controlling organic particle-size is completely different from conventional ones. The investigation results of the influences of Cu2+ on the optical properties and particle sizes of THP-1 in ethanol–water suspensions as well as the molecular stacking mode in the single-crystal of THP-1 indicate that the copper-induced fluorescence enhancement and particle-size decrease are expected to result from the coordination-induced dissociation of intermolecular O–H⋯O bonds connecting non-emissive groups. In addition, THP-1 shows no cytotoxicity in EC109 cells at concentrations below 30 μM. These useful and interesting properties of THP-1 are expected to be very helpful for new probe design, theoretical research on the relationship between intermolecular hydrogen bonds and optical properties, as well as practical applications in organic particle-size control and chemical/biological fluorescence probes.

We reported previously that a small molecule named CL-385319 could inhibit H5N1 influenza virus infection by targeting hemagglutinin, the envelope protein mediating virus entry. In the present study, a novel series of derivatives focused on the structural variation of CL-385319 were synthesized as specific inhibitors against the H5 subtype of influenza A viruses. These small molecules inhibited the low pH-induced conformational change of hemagglutinin, thereby blocking viral entry into host cells. Compound 1l was the most active inhibitor in this series with an IC50 of 0.22 μM. The structure–activity relationships analysis of these compounds showed that the 3-fluoro-5-(trifluoromethyl)benzamide moiety was very important for activity, and the –F group was a better substituent group than –CF3 group in the phenyl ring. The inhibitory activity was sensitive to the benzamide because the oxygen and hydrogen of the amide served as H-bond acceptor and donor, respectively.Graphical abstractAmong a series of derivatives inhibiting H5N1 influenza virus membrane fusion by targeting hemagglutinin, the most active inhibitor is 1l with an IC50 of 0.22 μM.Highlights► All of the 26 new compounds based on CL-385319 inhibit H5N1 pseudovirus. ► Compound 1l was the most active inhibitor with an IC50 of 0.22 μM ► Mechanism study showed that compound 1l target the H5-typed hemagglutinin. ► 3-Fluoro-5-(trifluoromethyl)benzamide is important for the inhibitory activity.

A series of tetra- and pentasubstituted polyfunctional dihydropyrroles 5 and 6 were synthesized via practical multicomponent reactions (MCRs) for research on their structure–activity relationship as caspase-3 inhibitors. Among 39 compounds evaluated, 14 of them exhibited inhibition against caspase-3 with IC50 ranging from 5 to 20 μM. The inhibitory activities of 5 and 6 depend on the nature of substituents on different positions. 5 and 6 possess a different scaffold from those previously reported and are the first caspase-3 inhibitors prepared via MCRs. The most active compounds 5k (IC50 = 5.27 μM) could therefore be used as a lead for the development of highly potent caspase-3 inhibitors as drug candidates for therapeutic agents by taking advantage of MCRs.Graphical abstractTetra- and pentasubstituted dihydropyrroles 5 and 6 were synthesized via practical one-pot multicomponent reactions (MCRs). 14 of them exhibited inhibition against caspase-3 with IC50 ranging from 5 to 20 μM.Highlights► The MCR scope for the synthesis of pentasubstituted polyfunctional dihydropyrroles 6 were expanded. ► Tetra- and pentasubstituted dihydropyrroles 5 and 6 are a novel series of caspase-3 inhibitors. ► The inhibitory activity of 5 and 6 depend on the nature of substituents on different positions.

Serpin A1 (α1-AT), the largest subgroup of serpins, presents in human plasma at high concentration and plays important regulatory roles in physiological and pathological processes. Accumulated evidence suggests that α1-AT may play a role in controlling HIV-1 infection. In this study, we designed and synthesized a set of short linear peptides derived from the C-terminal sequence of α1-AT. Since none of them showed significant anti-HIV-1activity, we proceeded to synthesize four short cyclic peptides having 7 amino acids, and we found that three of them exhibited significant anti-HIV-1 activity. One of these cyclic peptides, designated CPM, inhibited HIV-1 entry and infection at low μM level, indicating that these short cyclic peptides could serve as leads for the development of novel anti-HIV-1 therapeutics.

Evidence has shown that the p7, NS2 and NS3 genes affect the outcome of pegylated-IFN-α/ribavirin (PEG-IFN/RBV) combination therapy in different populations with HCV infections. Here, we test the hypothesis that diversity in the p7, NS2 and NS3 genes influences the probability of obtaining either a sustained (SVR) or non-sustained (non-SVR) viral response in Chinese patients with genotype 1b chronic hepatitis C. There were significantly more unique variations in the p7, NS2 and NS3 genes in the sequences from SVR than non-SVR patients. Inter-patient variations related to treatment outcome in NS3 were concentrated in the protease domain. There were no significant differences in the frequency of variations in the core, E1 and E2 proteins between the groups. In conclusion, increased amino acid sequence diversity in the p7, NS2 and NS3 genes is associated with an SVR to PEG-IFN/RBV therapy in Chinese patients with genotype 1b chronic hepatitis C.

Seasonal influenza epidemics and influenza pandemics caused by influenza A virus (IAV) has resulted in millions of deaths in the world. The development of anti-IAV vaccines and therapeutics is urgently needed for prevention and treatment of IAV infection and for controlling future influenza pandemics. Hemagglutinin (HA) of IAV plays a critical role in viral binding, fusion and entry, and contains the major neutralizing epitopes. Therefore, HA is an attractive target for developing anti-IAV drugs and vaccines. Here we have reviewed the recent progress in study of conformational changes of HA during viral fusion process and development of HA-based antiviral therapeutics and vaccines.

Icaritin is a native compound from Epimedium Genus, a traditional Chinese herbal medicine which is effective in treating asthma, autoimmune diseases and viral infections. In the present paper, the immunosuppressive effects of icaritin were found through in vitro and in vivo studies. Icaritin could dose-dependently inhibit murine CD4+ T cells proliferation stimulated with mitogens or specific antigen ovabumin (OVA). Icaritin at 0.25–25 μM could down-regulate T cell activation marker CD25 expression and inhibit IL-2 production. It could also reduce the Th1 cytokine IFN-γ production significantly if the T cells were activated by ConA or anti-CD3; while the inhibition of IL-4 secretion was only seen on anti-CD3 activated T cells treated with low concentrations of icaritin. In vivo study showed that treatment of icaritin at 10 mg/kg/day on mice could suppress the immune response with prolonged allograft skin survival. Further study demonstrated that it reduced the alloantigen-induced splenocytes proliferation and Th1/Th2 cytokines. It could also increase NF-AT luciferase activity in Jurkat-NF-AT-luc T cells. The above results suggested that icaritin might be used to treat Th1 dominated immune diseases by interfering T cells activation with mechanism different to CsA.Highlights► Icaritin could dose-dependently inhibit activated murine T cells proliferation. ► Icaritin could down-regulate CD25 expression and inhibit Th1 cytokines IL-2 and IFN-γ production. ► Icaritin could prolong murine allograft skin survival with mechanism different to CsA. ► Icaritin might be used to treat Th1 dominated immune diseases by interfering T cells activation.

Neurological complications associated with HIV-1 are being recognized as a common disorder in AIDS patients, especially patients with HIV-associated dementia (HAD). However, our knowledge of the complicated pathogenesis and clinical symptoms of HAD is limited by an incomplete understanding of the biology of HIV-1 in the nervous system. Therefore, this review focuses on the pathogenesis of HAD in the context of novel highly active antiretroviral therapy (HARRT) regimens.

The dysregulation of apoptosis is a key step in developing cancers, and mediates resistance to cancer therapy. Commitment to apoptosis is caused by permeabilization of the outer mitochondrial membrane, a process regulated by the interactions between different proteins of Bcl-2 family. Furthermore, Bcl-2 family proteins also bind to the endoplasmic reticulum, where they modulate autophagy, another important pathway regulating cell survival and death. Dysregulation of Bcl-2 family has been demonstrated in a wide spectrum of human cancers, including gastrointestinal cancers. Therefore, targeting the Bcl-2 family of proteins represents a promising therapeutic approach for these malignancies. Recent advances have yielded small molecules that have close structural or functional similarity to BH3-only proteins and are therefore named BH3 mimetics. Of these BH3 mimetics, obatoclax, (−)-gossypol, and ABT-263 are currently in clinical trials for multiple cancers. Growing evidence indicates that these BH3 mimetics not only induce apoptosis, but also regulate autophagy which may serve as a pro-survival or pro-death mechanism to counteract or mediate the cytotoxicity of BH3 mimetics. This review discusses the role of autophagy in cell-fate decision upon BH3 mimetics treatment. Further exploration of our understanding of the association between autophagy and cellular outcomes in response to BH3 mimetics treatment will likely offer improved therapies for patients with cancer.

Cisplatin is a chemotherapeutic drug widely used for the treatment of gastric cancer. The benefit of including COX-2-selective inhibitors in cisplatin-based regimens on anti-cancer effect remains uncertain. In the present study, celecoxib and SC-236 antagonized cisplatin-induced cytotoxicity and apoptosis, whereas indomethancin and nimesulide exerted no effect, implying a COX-2-independent mechanism. Celecoxib decreased whole-cell cisplatin accumulation and DNA platination, resulting from reduced influx. In addition, combined treatment did not elicit greater antitumor activity than cisplatin or celecoxib monotherapy in vivo in a gastric xenograft model. Therefore, treatment strategies with celecoxib in combination with cisplatin should act cautiously.

•EPs derived from HIV-1 gp120 significantly enhance HIV-1 infection.•EPs target the virus entry process to boost HIV-1 infection.•EPs suppress the anti-HIV-1 activity of ARVs.•EGCG antagonizes the EP-mediated enhancement of HIV-1 infection.•EPs might be effective agents to promote retroviral gene transfer.Amyloid fibrils play important roles in HIV-1 infection. We found peptides derived from the HIV-1 gp120 co-receptor binding region, which are defined as enhancing peptides (EPs), could form amyloid fibrils and remarkably enhance HIV-1 infection. EPs bound to the virus and promoted the interaction between HIV-1 and target cells. The antiviral efficacy of antiretroviral drugs (ARVs) was substantially impaired in the presence of EPs. Epigallocatechin gallate (EGCG) could both inhibit the formation of fibrils composed of EPs and counteract the EP-mediated enhancement of HIV-1 infection. Our findings identify viral derived amyloid fibrils that hold potential for biochemical applications.Structured summary of protein interactionsEP1 and EP1 bind by fluorescence technology (View interaction)EP2 and EP2 bind by fluorescence technology (View interaction)EP3 and EP3 bind by fluorescence technology (View interaction)SEVI and SEVI bind by fluorescence technology (View interaction)EP1 and EP1 bind by transmission electron microscopy (View interaction)EP2 and EP2 bind by transmission electron microscopy (View interaction)EP3 and EP3 bind by transmission electron microscopy (View interaction)SEVI and SEVI bind by transmission electron microscopy (View interaction)

Hydrogels have been widely studied in various biomedical applications, such as tissue engineering, cell culture, immunotherapy and vaccines, and drug delivery. Peptide-based nanofibers represent a promising new strategy for current drug delivery approaches and cell carriers for tissue engineering. This review focuses on the recent advances in the use of self-assembling engineered β-sheet peptide assemblies for biomedical applications. The applications of peptide nanofibers in biomedical fields, such as drug delivery, tissue engineering, immunotherapy, and vaccines, are highlighted. The current challenges and future perspectives for self-assembling peptide nanofibers in biomedical applications are discussed.

Racemic C6-unsubstituted tetrahydropyrimidines (THPs) are a series of fluorophores with a strong aggregation-induced emission (AIE) effect. However, they do not possess the structural features of conventional AIE compounds. In order to understand their AIE mechanism, here, the influences of the molecular packing mode and the conformation on the optical properties of THPs were investigated using seven crystalline polymorphs of three THPs (1–3). The racemic THPs 1–3 have low-conjugated and highly flexible molecular structures, and hence show practically no emission in different organic solvents. However, the fluorescence quantum yields of their polymorphs are up to 93%, and the maximum excitation (λex) and emission (λem) wavelengths of the polymorphs are long at 409 and 484 nm, respectively. Single-crystal structures and theoretical calculation of the HOMOs and LUMOs based on the molecular conformations of these polymorphs indicate that the polymorphs with the shortest λex and λem values possess a RS-packing mode (R- and S-enantiomers self-assemble as paired anti-parallel lines) and a more twisted conformation without through-space conjugation between the dicarboxylates, but the polymorphs with longer λex and λem values adopt a RR/SS-packing mode (R- and S-enantiomers self-assemble as unpaired zigzag lines) and a less twisted conformation with through-space conjugation between the dicarboxylates. The molecular conformations of 1–3 in all these polymorphs are stereo and more twisted than those in solution. Although 1–3 are poorly conjugated, the radiative rate constants (kr) of their polymorphs are as large as conventional fluorophores (0.41–1.03 × 108 s−1) because of improved electronic conjugation by both through-bond and through-space interactions. Based on the obtained results, it can be deduced that the strong AIE arises not only from the restriction of intramolecular motion but also from enhanced electronic coupling and radiatively-favored inter-crossed local excitation (LE) and intramolecular charge transfer (ICT) excitation states. The abnormal molecular structures, easily-controllable self-assembly of the R- and S-enantiomers, and the strong AIE effect make THPs very useful fluorophores for applications and theoretical research.

A sensitive and visible fluorescence-turn-on probe for the critical micelle concentration (CMC) determination of ionic surfactants has been developed based on practically no emission in micelles but strong aggregation-induced emission in solution of racemate tetrahydropyrimide THP-1. CMC values were determined via the inflexion with the strongest fluorescence intensity.