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1.
Lalitha Guruprasad 《Proteins》2020,88(11):1387-1393
Coronavirus disease 2019 (COVID-19) is a pandemic infectious disease caused by novel severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The SARS CoV-2 is transmitted more rapidly and readily than SARS CoV. Both, SARS CoV and SARS CoV-2 via their glycosylated spike proteins recognize the human angiotensin converting enzyme-2 (ACE-2) receptor. We generated multiple sequence alignments and phylogenetic trees for representative spike proteins of SARS CoV and SARS CoV-2 from various host sources in order to analyze the specificity in SARS CoV-2 spike proteins required for causing infection in humans. Our results show that among the genomes analyzed, two sequence regions in the N-terminal domain “MESEFR” and “SYLTPG” are specific to human SARS CoV-2. In the receptor-binding domain, two sequence regions “VGGNY“ and ”EIYQAGSTPCNGV” and a disulfide bridge connecting 480C and 488C in the extended loop are structural determinants for the recognition of human ACE-2 receptor. The complete genome analysis of representative SARS CoVs from bat, civet, human host sources, and human SARS CoV-2 identified the bat genome (GenBank code: MN996532.1) as closest to the recent novel human SARS CoV-2 genomes. The bat SARS CoV genomes (GenBank codes: MG772933 and MG772934) are evolutionary intermediates in the mutagenesis progression toward becoming human SARS CoV-2. 相似文献
2.
《Bioorganic & medicinal chemistry》2020,28(11):115492
Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition. 相似文献
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Intra- and interbreed genetic variations of mitochondrial DNA major non-coding regions in Japanese native dog breeds [Canis familiaris) 总被引:1,自引:0,他引:1
Mitochondrial DNA (mtDNA) major non-coding regions were amplified from 73 dogs of eight Japanese native dog breeds and from 21 dogs of 16 non-Japanese dog breeds by the polymerase chain reaction and their DNA sequences were determined. A total of 51 nucleotide positions within the non-coding region (969–972 base pairs) showed nucleotide variations of which 48 were caused by transition. These nucleotide substitutions were abundant in the region proximate to tRNAPro. In addition to the nucleotide substitutions, the dog mtDNA D-loop sequences had a heteroplasmic repetitive sequence (TACACGTÀCG) involving size variation. The DNA sequences of the non-coding region were classified into four different groups by phylogenetic analysis and the deepest branchpoints of this dog phylogeny was calculated to about 100 000 years before the present. Phylogenetic analysis showed that Japanese native dog breeds could not be clearly delimited as distinct breeds. Many haplotypes found in members of some clustering groups were seen in each dog breed, and interbreed nucleotide differences between Japanese dog breeds were almost the same as the intrabreed nucleotide diversities. 相似文献
6.
《Bioorganic & medicinal chemistry》2020,28(24):115819
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. 相似文献
7.
- Passiflora edulis f. flavicarpa is the most economically important species in the genus Passiflora. However, the origin of this yellow form of passion fruit remains unclear, being suggested as a hybrid (P. edulis f. edulis × P. ligularis) or wild mutant.
- Here, the origin and genomic relationships of P. edulis f. flavicarpa with some related species in the genus Passiflora (subgenera Decaloba and Passiflora) were investigated using genomic in situ hybridization (GISH). Genomic DNA of 18 species was used as probe, which was hybridized onto chromosomes of P. edulis f. flavicarpa.
- Of all genomic DNA probes tested, none allowed us to identify a specific chromosome set in P. edulis f. flavicarpa. Conversely, probes from the subgenus Passiflora, P. edulis f. edulis, P. alata, P. cincinnata, P. coccinea, P. nitida and P. vitifolia, produced intense and uniform hybridizations on all chromosomes of P. edulis f. flavicarpa. Moreover, probes from P. ligularis, P. foetida and P. sublanceolata produced more intense hybridizations in the terminal region of four chromosomes, corresponding to the DNAr 45S locus, and also dispersed, less intense, hybridization across all chromosomes. Probes from the subgenus Decaloba, P. biflora, P. capsularis, P. cervii, P. coriacea, P. micropetala, P. morifolia, P. rubra and P. suberosa, produced hybridizations restricted to the DNAr 45S sites.
- The hybrid origin of P. edulis f. flavicarpa could not be supported based on the GISH results, and it is suggested that this species is conspecific with P. edulis f. edulis, because the probe with DNA of this form hybridized strongly throughout the target genome. The other putative parent species, P. ligularis, showed only a distant relationship with the target genome. The results also suggest that species of the subgenus Passiflora share many repetitive sequences and that the relationship between subgenera Decaloba and Passiflora is very distant.
8.
Three series of bitobic arylpiperazine-phenyl-hexahydropyrazinoquino- lines analogues were designed, synthesizedand evaluated as a novel class of selective ligands for the dopamine D3 receptor. Compounds 15a (Ki of 11.7 ± 1.8 and 373 nM at D3 and D2, respectively), 15c (Ki of 5.49 and 264 nM at D3 and D2, respectively), 15e (Ki of 14.9 and 325 nM at D3 and D2, respectively), 15i (Ki of 13.8 and 401 nM at D3 and D2, respectively) and 15l (Ki of 13.6 and 870 nM at D3 and D2, respectively) were found to demonstrate good binding affinity and selectivity, and especially compound 15c showeda similar binding affinity and selectivity compared with the contrast drug BP897. 相似文献
9.
Aim Phylogenetic and phenotypic patterns among coexisting banksias (Banksia, Proteaceae) in the infertile, fire‐prone landscapes of south‐western Australia were examined for evidence of community structuring. It was expected that closely related species would be spatially clustered (underdispersed) as a consequence of widespread recent speciation, strong edaphic fidelity and low dispersability. We also expected that edaphic filtering would result in phenotypic clustering of traits related to habitat specialization and that competitive exclusion among closely related species with similar regeneration biology and growth form would result in phenotypic overdispersion of these latter traits. Location Southwest Australian Floristic Region (SWAFR). Methods Based on published data for coexistence (richness and frequency) of Banksia species at 40 sites in the three floristic provinces, phylogenetic, soil type and morphological mean pairwise distance and mean nearest taxon distance were calculated for each site and compared with null communities. Patterns of co‐occurrence were examined at the local and subregional (provincial) scales. Results Of the 40 sites assessed, 21–30 displayed phylogenetic clustering of Banksia species (5–11 significantly) such that, overall, co‐occurring taxa were more closely related than expected by chance. Banksias in the Transitional Rainfall and Southeast Coastal Provinces were more likely to display phylogenetic clustering than in the High Rainfall Province. A significant trend for phylogenetic clustering associated with edaphic specialization (27–30 sites) was observed, as well as a significant trend for phenotypic overdispersion associated with growth form (25–28 sites). Results for regeneration biology depended on the metric used. Main conclusions We demonstrate spatial clustering of closely related banksias at the local and provincial scales, consistent with their restricted distribution (recent widespread speciation, patchy habitat availability and limited dispersability) in this geologically old and stable region. The clustering of closely related species may also be a consequence of habitat filtering linked to edaphic fidelity in the SWAFR flora, while overdispersion in growth form suggests that functional divergence favours coexistence in Banksia communities. 相似文献
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