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1.
Eur J Med Chem ; 220: 113498, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33933756

RESUMO

Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 µM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.

2.
Eur J Med Chem ; 220: 113450, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33906049

RESUMO

A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4-3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.

3.
J Cell Mol Med ; 25(7): 3498-3510, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33682288

RESUMO

Transforming growth factor beta (TGF-ß) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-ß isoforms, including TGF-ß1, TGF-ß2 and TGF-ß3, remain unclear. Here, we demonstrated that all of the three TGF-ß isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-ß isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-ß isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-ß/SMAD signalling pathway-dependent and TGF-ß/SMAD signalling pathway-independent manners. TGF-ß isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-ß1 and TGF-ß2, not TGF-ß3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-ß isoforms in the HCV-related liver disease progression.

4.
Acta Pharm Sin B ; 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33723501

RESUMO

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a CFDA-approved macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

5.
ACS Appl Mater Interfaces ; 13(12): 14423-14432, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33733730

RESUMO

There has been a growing interest in the development of efficient flexible organic solar cells (OSCs) due to their unique capacity to provide energy sources for flexible electronics. To this end, it is required to design a compatible interlayer with low processing temperature and high electronic quality. In this work, we present that the electronic quality of the ZnO interlayer fabricated from a low-temperature (130 °C) sol-gel method can be significantly improved by doping an organic small molecule, TPT-S. The doped TPT-S, on the one hand, passivates uncoordinated Zn-related defects by forming N-Zn bonds. On the other hand, photoinduced charge transfer from TPT-S to ZnO is confirmed, which further fills up electron-deficient trap states. This renders ZnO improved electron transport capability and reduced charge recombination. By illuminating devices with square light pulses of varying intensities, we also reveal that an unfavorable charge trapping/detrapping process observed in low-temperature-processed devices is significantly inhibited after TPT-S doping. OSCs based on PBDB-T-2F:IT-4F with ZnO:TPT-S being the cathode interlayer yield efficiencies of 12.62 and 11.33% on rigid and flexible substrates, respectively. These observations convey the practicality of such hybrid ZnO in high-performance flexible devices.

6.
Poult Sci ; 100(2): 973-981, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33518151

RESUMO

It is known that nutrition and immunity are connected, but the mechanism is not very clear. Endogenous retroviruses (ERV) account for 8 to 10% of the human and mouse genomes and play an important role in some biological processes of animals. Recent studies indicate that the activation of ERV can affect the expression of the immunity- or inflammation-related genes, and the activities of ERV are subjected to regulation of many factors including nutritional factors. Therefore, we hypothesize that nutritional status can affect the expression of the immunity- or inflammation-related genes via ERV. To verify this hypothesis, the nutritional status of animals was altered by fasting or overfeeding, and the expression of intact ERV (ERVK18P, ERVK25P) and immunity- or inflammation-related genes (DDX41, IFIH1, IFNG, IRF7, STAT3) in the liver was determined by quantitative PCR, followed by overexpressing ERVK25P in goose primary hepatocytes and determining the expression of the immunity- or inflammation-related genes. The data showed that compared with the control group (no fasting), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the fasted chickens but decreased in the liver of the fasted geese. Moreover, compared with the control group (routinely fed), the expression of ERV and the immunity- or inflammation-related genes was increased in the liver of the overfed geese. In addition, overexpression of ERVK25P in goose primary hepatocytes can induce the expression of the immunity- or inflammation-related genes. In conclusion, these findings suggest that ERV mediate the effects of fasting and overfeeding on the expression of the immunity- or inflammation-related genes, the mediation varied with poultry species, and ERV and the immunity- or inflammation-related genes may be involved in the development of goose fatty liver. This study provides a potential mechanism for the connection between nutrition and immunity.


Assuntos
Retrovirus Endógenos/fisiologia , Jejum/fisiologia , Hiperfagia/genética , Aves Domésticas/genética , Animais , Galinhas , Hiperfagia/imunologia , Hiperfagia/patologia , Imunidade/fisiologia , Inflamação/genética , Inflamação/veterinária , Fígado/imunologia , Fígado/patologia , Camundongos , Aves Domésticas/imunologia
7.
Biochem Biophys Res Commun ; 545: 138-144, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33548627

RESUMO

The mRNA export flux through nuclear pore complexes (NPC) changes under DNA manipulation and hence affects protein translation. However, monitoring the flux of a specific mRNA in single live cell is beyond reach of traditional techniques. We developed a fluorescence-based detection method for measuring the export flux of mRNA through NPC in single live cell using a snapshot image, which had been tested on exogenous genes' expression in HeLa cells, with transfection or infection, and endogenous genes' expression in yeast cells, during incubation and carbon catabolite repression. With its speediness, explicitness and noninvasiveness, we believe that it would be valuable in direct monitoring of gene behavior, and the understanding of gene regulation at a single cell level.

8.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632712

RESUMO

OBJECTIVE: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells. CONCLUSION: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

9.
Biomaterials ; 268: 120614, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33360771

RESUMO

Antibacterial photodynamic therapy (aPDT) is of vital importance for the treatment of periodontal diseases due to its great potential on effective elimination of pathogenic bacteria via overwhelming reactive oxygen species (ROS) generation. However, the excessive ROS after the therapeutic process may impose an oxidative stress within periodontal pockets, consequently leading to an irreversible destroy in surrounding tissue and severely limit its biomedical applications. In this study, considering the contradiction between ROS in bacteriostasis and inflammation, the role of ROS in different temporal and spatial states has been fully studied. Accordingly, we have designed composite nanomaterials that can play ROS based aPDT and anti-inflammatory effect by eliminating ROS, taking account of different ratio of photosensitizer/ROS scavenger to realize a time-sequential manner. Herein, a simple multifunctional nanocomposite was fabricated by coating red light-excited photosensitizer chlorin e6 (Ce6) onto nanoceria, achieving simultaneous sterilization and inflammation elimination via a dual directional regulation effect. This nano-based platform could utilize the aPDT for antibacterial purpose in the first stage with red-light irradiation, and subsequently scavenge the residual ROS via nanoceria to modulate host immunity by down-regulating the M1 polarization (pro-inflammatory) of macrophages and up-regulating the M2 polarization (anti-inflammatory and regenerative) of macrophages. Moreover, the local ROS level induced by activated inflammation pathway can be adjusted in a very long time because of the charge conversion effect of CeO2. The regenerative potential of inflammatory surrounding tissues was improved in the animal model. Our strategy will open a new inspiration to fight against the defects of aPDT in the treatment of periodontal disease, even in the anti-infection therapy for the future clinical application.

10.
Front Oncol ; 10: 575261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262944

RESUMO

Purpose: We sought to develop diagnostic models incorporating mpMRI examination to identify PCa (Gleason score≥3+3) and CSPCa (Gleason score≥3+4) to reduce overdiagnosis and overtreatment. Methods: We retrospectively identified 784 patients according to inclusion criteria between 2016 and 2020. The cohort was split into a training cohort of 548 (70%) patients and a validation cohort of 236 (30%) patients. Age, PSA derivatives, prostate volume, and mpMRI parameters were assessed as predictors for PCa and CSPCa. The multivariable models based on clinical parameters were evaluated using area under the curve (AUC), calibration plots, and decision curve analysis (DCA). Results: Univariate analysis showed that age, tPSA, PSAD, prostate volume, MRI-PCa, MRI-seminal vesicle invasion, and MRI-lymph node invasion were significant predictors for both PCa and CSPCa (each p≤0.001). PSAD has the highest diagnostic accuracy in predicting PCa (AUC=0.79) and CSPCa (AUC=0.79). The multivariable models for PCa (AUC=0.92, 95% CI: 0.88-0.96) and CSPCa (AUC=0.95, 95% CI: 0.92-0.97) were significantly higher than the combination of derivatives for PSA (p=0.041 and 0.009 for PCa and CSPCa, respectively) or mpMRI (each p<0.001) in diagnostic accuracy. And the multivariable models for PCa and CSPCa illustrated better calibration and substantial improvement in DCA at threshold above 10%, compared with PSA or mpMRI derivatives. The PCa model with a 30% cutoff or CSPCa model with a 20% cutoff could spare the number of biopsies by 53%, and avoid the number of benign biopsies over 80%, while keeping a 95% sensitivity for detecting CSPCa. Conclusion: Our multivariable models could reduce unnecessary biopsy without comprising the ability to diagnose CSPCa. Further prospective validation is required.

11.
J Hazard Mater ; : 124218, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33092883

RESUMO

Increasing scientific findings show that the adverse health effects of PM2.5 are related not only to its mass but also PM2.5 sources and chemical compositions. Here, we conducted a comprehensive characterization and source apportionment of oxidative potential (OP) of water-soluble PM2.5 collected in Hong Kong for one year. Two OP indicators, namely dithiothreitol (DTT) consumption and ∙OH formation, were quantified. Six PM2.5 sources, i.e. secondary sulfate, biomass burning, secondary organic aerosol (SOA), vehicle emissions, marine vessels, and a metal-related factor, were apportioned and identified to be DTT active. The four primary sources accounted for 83.5% of DTT activity of water-soluble PM2.5, with the metal-related factor and marine vessels as the leading contributors. However, only three sources, i.e. metal-related factor, vehicle emissions, and SOA, showed ∙OH generation ability, with a predominant contribution of 96.2% from the two primary sources, especially the metal-related factor (84.5%). Based on the source apportionment results, we further evaluate the intrinsic OP of water-soluble PM2.5 from each source. Marine vessels exhibited the highest intrinsic DTT activity; while metal-related factor was most effective in ∙OH generation.

12.
Curr Med Chem ; 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778020

RESUMO

Andrographolide, the main bioactive component separated from Andrographis paniculata in 1951, have been scrutinized with modern drug discovery approach for anti-inflammatory properties since 1984. Identifying new uses for existing drugs can be facilitated by evidence linking them to known or yet undiscovered drug targets and human disease states to develop new therapeutic indications. Afterwards, a wide spectrum of biological properties of andrographolide such as anti-cancer, antibacterial, antiviral, hepatoprotective, antioxidant, anti-malarial, anti-atherosclerosis were also reported. However, poor water solubility and instability limit its clinical application. it becomes crucial to enhance its pharmacological function and find new treatment for more diseases. Therefore, this article reviews the major recent developments in andrographolide, including repurposing application in different diseases and underlying mechanisms, particularly focusing on pharmacological enhancement of andrographolide such as derivatives, chemical modifications with potent biological activity and drug delivery. The repurposing and pharmacological enhancement of andrographolide would not only have exciting therapeutic potential to different diseases to facilitate drug marketing, but also decrease the burden on health economies worldwide.

13.
Medicine (Baltimore) ; 99(30): e20920, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791672

RESUMO

BACKGROUND: Accumulating emerging studies have demonstrated that systemic inflammation can obviously affect tumor occurrence and progression. Nevertheless, the prognostic value of hematological inflammation biomarkers in bladder cancer is controversial. Thus, we conducted a meta-analysis to evaluate the key hematological biomarkers with various clinical outcomes in bladder cancer. METHODS: We used online databases PUBMED and EMBASE to search relevant studies published prior to August 2019. After collecting the basic characteristics and prognostic data from the studies included, overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) were used as primary results. Subgroup analyses were performed according to ethnicity, the number of samples, survival outcomes, the value of cut-off, follow-up time and metastasis stage. RESULTS: Thirty-three independent studies with 17,087 bladder cancer patients were added in the present analysis. The collected results showed that the increased neutrophil-to-lymphocyte ratio was associated with a poor OS (hazard ratio [HR] = 1.48, 95% confidence interval [CI]: 1.32-1.67, P < .00001), CSS (HR = 1.71, 95%CI: 1.35-2.18, P < .0001) and PFS (HR = 1.59, 95%CI: 1.38-1.83, P < .00001). Additionally, the elevated platelet-to-lymphocyte ratio was related to a poor OS (HR = 1.29, 95% CI: 1.07-1.54, P = .007), CSS (HR = 1.14, 95%CI = 0.98-1.34, P = .02) and PFS (HR = 1.2, 95%CI: 1.08-1.34, P = .0008). Moreover, a decreased lymphocyte-to-monocyte ratio was associated with a poor OS (HR = 0.77, 95% CI: 0.70-0.84, P = .001), CSS (HR = 0.76, 95%CI: 0.70-0.84). An elevated modified Glasgow prognostic score was also associated with a poor OS (HR = 2.71, 95%CI: 1.08-2.82, P = .003), CSS (HR = 1.50, 95%CI: 0.56-4.05) and PFS (HR = 1.52, 95%CI: 1.23-1.88, P = .001). CONCLUSIONS: Our study indicated that the pretreatment hematological biomarkers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and modified Glasgow prognostic score) were predicative biomarkers of prognosis in bladder cancer patients. Further research is needed to conduct further prospective and multicenter studies to confirm our findings.


Assuntos
Carcinoma/sangue , Neoplasias da Bexiga Urinária/sangue , Biomarcadores/sangue , Carcinoma/mortalidade , Humanos , Contagem de Linfócitos , Contagem de Plaquetas , Neoplasias da Bexiga Urinária/mortalidade
14.
Proc Natl Acad Sci U S A ; 117(36): 22237-22248, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32839316

RESUMO

NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonad-specific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro. Physiologically, knock out of Nlrp14 resulted in reproductive failure in both female and male mice. In adult male mice, Nlrp14 knockout (KO) inhibited differentiation of spermatogonial stem cells (SSCs) and meiosis, resulting in trapped SSCs in early stages, severe oligozoospermia, and sperm abnormality. Mechanistically, NLRP14 promoted spermatogenesis by recruiting a chaperone cofactor, BAG2, to bind with HSPA2 and form the NLRP14-HSPA2-BAG2 complex, which strongly inhibited ChIP-mediated HSPA2 polyubiquitination and promoted its nuclear translocation. Finally, loss of HSPA2 protection and BAG2 recruitment by NLRP14 was confirmed in a human nonsense germline variant associated with male sterility. Together, our data highlight a unique proteasome-mediated, noncanonical function of NLRP14 in PGCLC differentiation and spermatogenesis, providing mechanistic insights of gonad-specific NLRs in mammalian germline development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Chaperonas Moleculares/metabolismo , Espermatogênese/genética , Transporte Ativo do Núcleo Celular/genética , Transporte Ativo do Núcleo Celular/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Células-Tronco Germinativas Adultas/fisiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Feminino , Deleção de Genes , Regulação da Expressão Gênica/fisiologia , Variação Genética , Células Germinativas , Proteínas de Choque Térmico HSP70/genética , Humanos , Infertilidade Masculina/genética , Masculino , Camundongos , Chaperonas Moleculares/genética , Nucleosídeo-Trifosfatase/genética , Nucleosídeo-Trifosfatase/metabolismo , Espermatogênese/fisiologia
15.
Int J Biol Macromol ; 164: 1275-1283, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682042

RESUMO

The endogenous rutin-degrading enzymes (RDEs) in Tartary buckwheat (TB) considerably limit the development of TB functional foods. In this study, three thermal treatments, including superheated steam (SS), saturated steam (ST), and far-infrared drying (FID), were used to inactivate RDEs in TB. Results showed that SS and ST could efficiently inactivate RDEs, whereas FID could not. The extractable rutin contents in TB were increased by 52.3% and 12.3% by SS and ST, respectively, with 90 s of treatment time. Furthermore, the properties of phenolics and starch were used to evaluate the influence of thermal inactivation on TB. Results showed that the soluble phenolic compounds contents in TB were significantly improved (p < 0.05) by SS. The bound phenolic compounds contents were decreased after SS and ST treatments. The change in antioxidant properties was consistent with that of phenolics and flavonoids. Besides, the starch in SS- and ST-treated TB achenes had higher relative crystallinity, setback, transition temperatures, rapidly digestible starch, and slowly digestible starch contents, but a lower ratio of 1047 cm-1/1022 cm-1, peak viscosity, breakdown, gelatinization enthalpy, and resistant starch contents, than native TB starch. In conclusion, SS was a better method for the inactivation of RDEs than ST.

16.
Eur J Pharmacol ; 883: 173323, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622669

RESUMO

Aloperine, a natural alkaloid isolated from the Chinese traditional herb Sophora alopecuroides, is a broad-spectrum antiviral agent with anti-inflammatory activity. Here, we found that aloperine effectively inhibited hepatitis C virus (HCV) propagation in Huh7.5 cells and primary human hepatocytes without cytotoxicity, and it blocked HCV cell-to-cell viral transmission. The antiviral mechanism evidence demonstrated that aloperine inhibits HCV internalisation from endocytosis to the membrane fusion process, and the target may be associated with host factors. Aloperine additively inhibited HCV propagation with direct-acting antivirals (DAAs) and was effective against HCV variants resistant to known DAAs. Therefore, aloperine might be a natural lead compound for the development of innovative antivirals, and the combined use of aloperine with DAAs might contribute to eliminating liver diseases caused by HCV infection.

17.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
18.
Bioorg Med Chem ; 28(16): 115623, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690263

RESUMO

Newly designed HIV-1 protease inhibitors that maximize interactions with the protein backbone, especially in the form of hydrogen bonds, may enhance the antiviral potency of these compounds and minimize acquisition of drug-resistant mutations. Herein, we described a series of new HIV-1 PIs containing phenols as the P2 ligands and chiral isopropanol as the P1' ligands, in combination with 4-trifluoromethylphenylsulfonamide or 4-nitrophenylsulfonamide as the P2' ligands. And most of these compounds exhibited nanomolar inhibitory potency. In particular, inhibitors 13c and 13e with 4-trifluoromethylphenylsulfonamide as the P2' ligand and (R) - isopropanol as the P1' ligand, exhibited antiviral IC50 values of 1.64 nM and 2.33 nM, respectively. Furthermore, they also showed remarkable activity against wild-type and DRV-resistant HIV-1 variants that raised the prospect of designing more effective PIs further.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32596233

RESUMO

Nowadays, the heavy burden of oral diseases such as dental caries, periodontitis, endodontic infections, etc., and their consequences on the patients' quality of life indicate a strong need for developing effective therapies. Bacterial infections played an important role in the field of oral diseases, in-depth insight of such oral diseases have given rise to the demand for antibacterial therapeutic strategies. Recently, microporous frameworks have attracted tremendous interest in antibacterial application due to their well-defined porous structures for drug delivery. In addition, intensive efforts have been made to enhance the antibacterial performance of microporous frameworks, such as ion doping, photosensitizer incorporation as building blocks, and surface modifications. This review article aims on the major recent developments of microporous frameworks for antibacterial applications against oral diseases. The first part of this paper puts concentration on the cutting-edge researches on the versatile antibacterial strategies of microporous materials via drug delivery, inherent activity, and structural modification. The second part discusses the antibacterial applications of microporous frameworks against oral diseases. The applications of microporous frameworks not only have promising therapeutic potential to inhibit bacterial plaque-initiated oral infectious diseases, but also have a wide applicability to other biomedical applications.

20.
ACS Med Chem Lett ; 11(6): 1196-1204, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32551001

RESUMO

Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme Ki of 0.092 nM and 0.21 nM, as well as antiviral IC50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94% and 91%, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.

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