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Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443484


The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28-65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0-3.5 µM) and binding affinities (Kd = 0.9-7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.

Venenos de Crotalídeos/química , Dimerização , Papaína/antagonistas & inibidores , Peptídeos/química , Peptídeos/farmacologia , SARS-CoV-2/enzimologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Papaína/química , Papaína/metabolismo , Peptídeos/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Conformação Proteica , SARS-CoV-2/efeitos dos fármacos
Int J Biol Macromol ; 120(Pt B): 1893-1905, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30290254


Esterases are widely applied in industrial processes due to their versatility, regio- and enantioselectivity, lack of cofactors and stability in organic solvents. Bacillus licheniformis, a microorganism frequently used in industrial and biotechnological applications such as dairy, baking, beverage, pulp and paper, detergent and cosmetics production, organic synthesis and waste management, is a promising source of esterases. Here we describe the biochemical and biophysical characterization of B. licheniformis carboxylesterase BlEst1 and its SAXS-derived molecular envelope. BlEst1 has optimal hydrolytic activity against p­nitrophenyl acetate at pH 7.0 and 40 °C. Furthermore, BlEst1 is stable in different organic solvents such as methanol, isopropanol and butanol. The BlEst1 homology model reveals a typical α/ß hydrolase core with an adjacent auxiliary domain, snuggly fitting the experimental low-resolution SAXS molecular envelope. Moreover, BlEst1 maintained considerable part of its activity in the presence of up to 5 M NaCl and its thermal stability was significantly enhanced by the presence of salt, revealing its halotolerant character. The ability to work under harsh conditions makes BlEst1 an interesting candidate for industrial applications.

Bacillus licheniformis/enzimologia , Carboxilesterase/química , Carboxilesterase/metabolismo , Estabilidade Enzimática , Modelos Moleculares , Filogenia , Conformação Proteica , Homologia de Sequência de Aminoácidos , Estereoisomerismo , Especificidade por Substrato , Temperatura
Front Genet ; 9: 359, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250479


Introgression should no longer be considered as rare a phenomenon as once thought, since several studies have recently documented gene flow between closely related and radiating species. Here, we investigated evolutionary relationships among three closely related species of fruit flies of the Anastrepha fraterculus group (Anastrepha fraterculus, A. obliqua and A. sororcula). We sequenced a set of 20 genes and implemented a combined populational and phylogenetic inference with a model selection approach by an ABC framework in order to elucidate the demographic history of these species. The phylogenetic histories inferred from most genes showed a great deal of discordance and substantial shared polymorphic variation. The analysis of several population and speciation models reveal that this shared variation is better explained by introgression rather than convergence by parallel mutation or incomplete lineage sorting. Our results consistently showed these species evolving under an isolation with migration model experiencing a continuous and asymmetrical pattern of gene flow involving all species pairs, even though still showed a more closely related relationship between A. fraterculus and A. sororcula when compared with A. obliqua. This suggests that these species have been exchanging genes since they split from their common ancestor ∼2.6 MYA ago. We also found strong evidence for recent population expansion that appears to be consequence of anthropic activities affecting host crops of fruit flies. These findings point that the introgression here found may have been driven by genetic drift and not necessary by selection, which has implications for tracking and managing fruit flies.

Genome Biol Evol ; 10(1): 380-395, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346618


Several studies have demonstrated that genes differentially expressed between sexes (sex-biased genes) tend to evolve faster than unbiased genes, particularly in males. The reason for this accelerated evolution is not clear, but several explanations have involved adaptive and nonadaptive mechanisms. Furthermore, the differences of sex-biased expression patterns of closely related species are also little explored out of Drosophila. To address the evolutionary processes involved with sex-biased expression in species with incipient differentiation, we analyzed male and female transcriptomes of Anastrepha fraterculus and Anastrepha obliqua, a pair of species that have diverged recently, likely in the presence of gene flow. Using these data, we inferred differentiation indexes and evolutionary rates and tested for signals of selection in thousands of genes expressed in head and reproductive transcriptomes from both species. Our results indicate that sex-biased and reproductive-biased genes evolve faster than unbiased genes in both species, which is due to both adaptive pressure and relaxed constraints. Furthermore, among male-biased genes evolving under positive selection, we identified some related to sexual functions such as courtship behavior and fertility. These findings suggest that sex-biased genes may have played important roles in the establishment of reproductive isolation between these species, due to a combination of selection and drift, and unveil a plethora of genetic markers useful for more studies in these species and their differentiation.

Evolução Molecular , Genes de Insetos , Tephritidae/genética , Animais , Feminino , Fluxo Gênico , Masculino , Isolamento Reprodutivo , Seleção Genética , Caracteres Sexuais , Tephritidae/fisiologia , Transcriptoma