- An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. [Journal Article]
- DDDrug Dev Res 2018 Mar 23
- Hit, Lead & Candidate Discovery In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine...
Hit, Lead & Candidate Discovery In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine oxidase (MAO) enzymes. To expand on these series and to further derive structure-activity relationships (SARs) for MAO inhibition, in the present study we synthesized additional homologs and related analogs of these chemical classes. Analyzes of the MAO inhibition properties of the synthesized compounds show that among the pyrrolo[3,4-f]indole-5,7-dione derivatives good potency MAO inhibitors exist as exemplified by 10, which possesses IC50values for the inhibition of MAO-A and MAO-B of 0.023 and 0.178 µM, respectively. Among thirteen pyrrolo[3,4-f]indole-5,7-diones, nine compounds exhibit IC50values for the inhibition of an MAO isoform in the submicromolar range. It may be concluded that active MAO inhibitors, such as 10 represent suitable leads for the development of drugs for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. MAO inhibitors are also of interest for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.
- Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA. [Journal Article]
- JBJ Biol Chem 2018 Mar 22
- Cytosine methylation is a well characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-contain...
Cytosine methylation is a well characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-containing DNAs, are recognized by methyl-CpG-binding protein 2 (MeCP2) to regulate gene expression in neuron development. However, the molecular mechanism involved in the binding of methyl-CpG-binding domain (MBD) of MeCP2 to these different DNA motifs is unclear. Here, we systematically characterized the DNA-binding selectivity of the MBDs in MeCP2 and MBD1-4 with isothermal titration calorimetry-based binding assays, mutagenesis studies, and X-ray crystallography. We found that the MBD domains of MeCP2 and MBD1-4<br />bind mCG-containing DNAs independently of the sequence outside the mCG dinucleotide. Moreover, some 1 MBDs bound to both methylated and unmethylated CA dinucleotide-<br />containing DNAs, with a preference for the CAC sequence motif. We also found that MBD domains bind to mCA or nonmethylated CA DNA by recognizing the complementary TG dinucleotide, which is consistent with an overlooked ligand of MeCP2, i.e., the matrix/scaffold attachment regions (MARs/SARs) with a consensus sequence of 5'-GGTGT-3', which was<br />identified in early 1990s. Our results also explain why MeCP2 exhibits similar binding affinity to both mCAand hmCA-containing dsDNAs. In summary, our results suggest that in addition to mCG sites, unmethylated CA or TG sites also serve as DNA-binding sites for MeCP2 and other MBDcontaining proteins. This discovery expands the genome-wide activity of MBD-containing proteins in gene regulation.
- Biyuanling suppresses the toluene-2, 4-diisocyanate induced allergic rhinitis in guinea pigs. [Journal Article]
- OOncotarget 2018 Feb 27; 9(16):12620-12629
- Allergic rhinitis (AR), one of the common diseases of the upper respiratory system, is associated with high risk of nasopharyngeal carcinoma. Biyuanling Granules (BLG), a formulated preparation of tr...
Allergic rhinitis (AR), one of the common diseases of the upper respiratory system, is associated with high risk of nasopharyngeal carcinoma. Biyuanling Granules (BLG), a formulated preparation of traditional Chinese medicine, has been used in China for treatment of AR for more than a decade; however, its exact action against allergic rhinitis and the mechanism involved remain unclear. In this study, we studied the effects of BLG on allergic rhinitis induced by toluene-2, 4- diisocyanate (TDI) in guinea pigs. The anti-AR effects of BLG were evaluated by behavior observations, histological examinations of the nasal tissues stained with hematoxylin and eosin staining (H&E), immunohistochemical analyses of pulmonary surfactant associated protein (SP), Bcl-2 Associated X Protei (Bax), tumor necrosis factor (TNF-α) and vascular cell adhesion molecule-1 (VCAM-1) in the nasal mucosa, and serum tests of interleukin-4 (IL-4) and human SARS-specific immunoglobulin (SIgE) levels. We observed that in the AR-positive animals treated with BLG, the symptom scores were significantly higher (P< 0.01), the nasal mucosa edemas and inflammatory infiltrates were significantly alleviated (P< 0.01) and the serum IL-4 and SIgE levels were significantly decreased (P< 0.05) as compared with the control group. Immunohistochemical examinations of the nasal mucosa demonstrated that the expressions of TNF-α, SP and VCAM-1 were significantly decreased (P< 0.01), whereas Bax expression was increased in the BLG treatment groups (P< 0.05). These results indicate that BLG can effectively suppress the TDI-induced AR, and that the protective effects of BLG were associated with reductions of TNF-α, SP and VCAM-1, and an elevation of Bax, suggesting that BLG exerts its AR-suppressive effects through inhibition of inflammatory response.
- The discovery of novel diarylpyri(mi)dine derivatives with high level activity against a wide variety of HIV-1 strains as well as against HIV-2. [Journal Article]
- BMBioorg Med Chem 2018 Mar 03
- By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthe...
By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC50in the range of 1.36 nM-29 nM, which is much better than those of nevirapine (NVP, EC50 = 125.42 nM) and azidothymidine (AZT, EC50 = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC50values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture.
- Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. [Journal Article]
- JGJ Gen Virol 2018 Mar 20
- Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavir...
Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.
- Design, synthesis and cytotoxic effects of curcuminoids on HeLa, K562, MCF-7 and MDA-MB-231 cancer cell lines. [Journal Article]
- CCChem Cent J 2018 Mar 19; 12(1):31
- CONCLUSIONS: Curcuminoids with diferuloyl(4-hydroxy-3-methoxycinnamoyl) moiety with mono carbonyl exhibiting potential cytotoxic properties. The compound 14 was exhibited (IC50 = 3.02 ± 1.20 and 1.52 ± 0.60 µg/mL) against MCF-7 and MDA-MB-231 breast cancer cell lines.
- Behaviors, movements, and transmission of droplet-mediated respiratory diseases during transcontinental airline flights. [Journal Article]
- PNProc Natl Acad Sci U S A 2018 Mar 19
- With over 3 billion airline passengers annually, the inflight transmission of infectious diseases is an important global health concern. Over a dozen cases of inflight transmission of serious infecti...
With over 3 billion airline passengers annually, the inflight transmission of infectious diseases is an important global health concern. Over a dozen cases of inflight transmission of serious infections have been documented, and air travel can serve as a conduit for the rapid spread of newly emerging infections and pandemics. Despite sensational media stories and anecdotes, the risks of transmission of respiratory viruses in an airplane cabin are unknown. Movements of passengers and crew may facilitate disease transmission. On 10 transcontinental US flights, we chronicled behaviors and movements of individuals in the economy cabin on single-aisle aircraft. We simulated transmission during flight based on these data. Our results indicate there is low probability of direct transmission to passengers not seated in close proximity to an infectious passenger. This data-driven, dynamic network transmission model of droplet-mediated respiratory disease is unique. To measure the true pathogen burden, our team collected 229 environmental samples during the flights. Although eight flights were during Influenza season, all qPCR assays for 18 common respiratory viruses were negative.
- Monoclonal Antibodies and Antibody Like Fragments Derived from Immunised Phage Display Libraries. [Journal Article]
- AEAdv Exp Med Biol 2017; 1053:99-117
- Morbidity and mortality associated with infectious diseases are always on the rise, especially in poorer countries and in the aging population. The inevitable, but unpredictable emergence of new infe...
Morbidity and mortality associated with infectious diseases are always on the rise, especially in poorer countries and in the aging population. The inevitable, but unpredictable emergence of new infectious diseases has become a global threat. HIV/AIDS, severe acute respiratory syndrome (SARS), and the more recent H1N1 influenza are only a few of the numerous examples of emerging infectious diseases in the modern era. However despite advances in diagnostics, therapeutics and vaccines, there is need for more specific, efficacious, cost-effective and less toxic treatment and preventive drugs. In this chapter, we discuss a powerful combinatorial technology in association with animal immunisation that is capable of generating biologic drugs with high affinity, efficacy and limited off-site toxicity, and diagnostic tools with great precision. Although time consuming, immunisation still remains the preferred route for the isolation of high-affinity antibodies and antibody-like fragments. Phage display is a molecular diversity technology that allows the presentation of large peptide and protein libraries on the surface of filamentous phage. The selection of binding fragments from phage display libraries has proven significant for routine isolation of invaluable peptides, antibodies, and antibody-like domains for diagnostic and therapeutic applications. Here we highlight the many benefits of combining immunisation with phage display in combating infectious diseases, and how our knowledge of antibody engineering has played a crucial role in fully exploiting these platforms in generating therapeutic and diagnostic biologics towards antigenic targets of infectious organisms.
- A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling. [Journal Article]
- ACACS Chem Biol 2018 Mar 19
- We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discov...
We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discovering probes for immunology research. We used high content screening to measure the translocation from the cytoplasm to nucleus of IRF3 and NFkB in primary human macrophages; these transcription factors play a critical role in the activation of STING and other pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of these compounds did not cause activation of downstream pathways. Screening for antagonists of the STING pathway yielded multiple kinase inhibitors, some of which inhibit kinases not previously known to regulate the activity of this pathway. Structure-activity relationships (SARs) and subsequent chemical proteomics experiments suggested that MAPKAPK5 (PRAK) is a kinase that regulates IRF3 translocation in human macrophages. Our work establishes a high content screening approach for measuring pro-inflammatory pathways in human macrophages and identifies novel ways to inhibit such pathways; among the targets of the screen are several molecules that may merit further development as anti-inflammatory drugs.
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- Evaluation of Antibody-Dependent Enhancement of SARS-CoV Infection in Rhesus Macaques Immunized with an Inactivated SARS-CoV Vaccine. [Letter]
- VSVirol Sin 2018 Mar 14