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1.
chemRxiv; 2022.
Preprint em Inglês | ChemRxiv | ID: ppcovidwho-334508

RESUMO

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida, were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (1), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute stereochemistry was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.

2.
chemRxiv; 2022.
Preprint em Inglês | ChemRxiv | ID: ppcovidwho-333450

RESUMO

The design and synthesis of a series of peptide derivatives based on a short ACE2 alpha-helix 1 epitope and subsequent [i - i+4] stapling of the secondary structure resulted in the identification of a 9-mer peptide capable to compete with recombinant ACE2 towards Spike RBD in the micromolar range. Specifically, SARS-CoV-2 Spike inhibitor screening based on colorimetric ELISA assay and structural studies by circular dichroism showed the ring-closing metathesis cyclization being capable to stabilize the helical structure of the 9-mer 34-HEAEDLFYQ-42 epitope better than the triazole stapling via click chemistry. The results are preliminary for the development of small molecule stapled peptides capable of blocking the key ACE2-Spike S1 protein-protein interaction.

3.
Pure and Applied Chemistry ; 0(0):10, 2022.
Artigo em Inglês | Web of Science | ID: covidwho-1765566

RESUMO

From the receptor-binding domain (RBD) of the SARS-CoV-2 virus, which causes coronavirus disease 2019 (COVID-19), a RBD-hFc fusion protein was obtained at the Center of Molecular Immunology (Havana, Cuba). This fusion protein was used in the construction of a diagnostic device for COVID-19 called Ultramicroenzyme-Linked Immunosorbent Assay (UMELISA)-SARS-CoV-2-IgG and it is currently been used in the studies of biological activity of the Cuban vaccine Abdala (CIGB-66). In this work, Circular Dichroism (CD) is used to characterize this protein. Using Far Ultraviolet Circular Dichroism (FAR-UV CD), it was determined that the protein has a secondary structure in the form of a sheet-beta fundamentally. Using this technique, a thermodynamic study was carried out and it was determined that the melting temperature (Tm) of the protein is 71.5 degrees C. Information about the tertiary structure of the protein was obtained using Near Ultraviolet Circular Dichroism (NEAR-UV CD) and Molecular Fluorescence;they indicates that the protein has a three-dimensional folding associated with the aromatic amino acids in its structure, where tryptophan (Trp) is located inside the folded structure of the protein while tyrosine (Tyr) is exposed to the solvent.

4.
J Mol Graph Model ; 108: 107999, 2021 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1330984

RESUMO

Bioactive peptides derived from food proteins are becoming increasingly popular due to the growing awareness of their health-promoting properties. The structure and mechanism of anti-cancer action of pentapeptide Glu-Gln-Arg-Pro-Arg (EQRPR) derived from a rice bran protein are not known. Theoretical and experimental methods were employed to fill this gap. The conformation analysis of the EQRPR pentapeptide was performed first and the obtained lowest energy conformer was optimized. The experimental structural data obtained by FTIR and CD spectroscopies agree well with the theoretical results. d-isomer introduced one-by-one to each position and all D-isomers of the peptide were also examined for its possible anti-proteolytic and activity enhancement properties. The molecular docking revealed avid binding of the pentapeptide to the integrins α5ß1 and αIIbß3, with Kd values of 90 nM and 180 nM, respectively. Moreover, the EQRPR and its D-isomers showed strong binding affinities to apo- and holo-forms of Mpro, spike glycoprotein, ACE2, and dACE2. The predicted results indicate that the pentapeptide may significantly inhibit SARS-CoV-2 infection. Thus, the peptide has the potential to be the leading molecule in the drug discovery process as having multifunctional with diverse biological activities.


Assuntos
COVID-19 , Oryza , Humanos , Simulação de Acoplamento Molecular , Oligopeptídeos , SARS-CoV-2
5.
J Biomol Struct Dyn ; 40(3): 982-994, 2022 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1214145

RESUMO

Human C5a (hC5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection. hC5a has been associated with the pathogenesis of many chronic and acute diseases, due to its proven ability in triggering the 'cytokine storm', by binding to its cognate receptor C5aR, expressed in myriad of tissues. Given the pleiotropic downstream function of hC5a, it is logical to consider the hC5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive hC5a, by implementing the repurposing strategies for FDA-approved drugs. Indeed, the proof of principle biophysical studies published recently is encouraging, which strongly supports the potential of this strategy. Considering BSA-carprofen as a reference model system, the current study further explores the inherent conformational plasticity of hC5a and its effect in accommodating more than one drug molecule cooperatively at multiple sites. The data generated by recruiting a battery of experimental and computational biology techniques strongly suggest that hC5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki ∼ 0.5 µM and Ki ∼ 3.58 µM on its surface at non-analogous sites. The study hints at exploration of polypharmacology approach, as a new avenue for discovering synergistic drug molecule pairs, or drug molecules with 'broad-range' binding affinity for targeting the different 'hot spots' on hC5a, as an alternative combination therapy for possible management of the 'cytokine storm'-related inflammatory diseases, like COVID19.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Cloridrato de Raloxifeno , COVID-19/tratamento farmacológico , Complemento C5a/química , Síndrome da Liberação de Citocina , Humanos , Cloridrato de Raloxifeno/farmacologia , Receptor da Anafilatoxina C5a , Receptores de Complemento , SARS-CoV-2
6.
Comput Biol Chem ; 92: 107482, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-1163580

RESUMO

Complement system plays a dual role; physiological as well as pathophysiological. While physiological role protects the host, pathophysiological role can substantially harm the host, by triggering several hyper-inflammatory pathways, referred as "hypercytokinaemia". Emerging clinical evidence suggests that exposure to severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), tricks the complement to aberrantly activate the "hypercytokinaemia" loop, which significantly contributes to the severity of the COVID19. The pathophysiological response of the complement is usually amplified by the over production of potent chemoattractants and inflammatory modulators, like C3a and C5a. Therefore, it is logical that neutralizing the harmful effects of the inflammatory modulators of the complement system can be beneficial for the management of COVID19. While the hunt for safe and efficacious vaccines were underway, polypharmacology based combination therapies were fairly successful in reducing both the morbidity and mortality of COVID19 across the globe. Repurposing of small molecule drugs as "neutraligands" of C5a appears to be an alternative for modulating the hyper-inflammatory signals, triggered by the C5a-C5aR signaling axes. Thus, in the current study, few specific and non-specific immunomodulators (azithromycin, colchicine, famotidine, fluvoxamine, dexamethasone and prednisone) generally prescribed for prophylactic usage for management of COVID19 were subjected to computational and biophysical studies to probe whether any of the above drugs can act as "neutraligands", by selectively binding to C5a over C3a. The data presented in this study indicates that corticosteroids, like prednisone can have potentially better selectively (Kd ∼ 0.38 µM) toward C5a than C3a, suggesting the positive modulatory role of C5a in the general success of the corticosteroid therapy in moderate to severe COVID19.


Assuntos
COVID-19/tratamento farmacológico , Complemento C5a/antagonistas & inibidores , Simulação de Acoplamento Molecular , Prednisona/química , SARS-CoV-2 , Sítios de Ligação , COVID-19/patologia , Complemento C5a/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligação Proteica , Conformação Proteica
7.
Int J Biol Macromol ; 172: 418-428, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1033569

RESUMO

The major antioxidant enzyme catalase is downregulated and the enzyme activity is compromised in various disease conditions such as malarial and cancer. Hence, the restoration and protection of catalase is a promising therapeutic strategy in disease management. In the present study, for the first time we have demonstrated the protective role of well-known anti-malarial drug Artemisinin (ART) on the time and temperature-induced degradation of bovine liver catalase (BLC) activity. The findings at different time intervals and at higher temperature showed the protective role of ART on BLC activity. Molecular docking studies suggested specific binding of ART on BLC through heme group interface which was further supported by cyclic voltammetry and dynamic light scattering study. The stabilization of BLC in presence of ART was mediated through forming a BLC-ART complex with reduced and shifted electrochemical peak and increased hydrodynamic diameter. ART substantially prevents the temperature-induced reduction in α-helical content with simultaneous increment in other secondary structures like antiparallel, parallel, ß-turn and random coils. Nevertheless, the protective role of ART was accepted from the enhanced thermal stability and increased Tm value of BLC in presence of ART at higher temperatures. Our results uncover the mechanism of interaction between ART with BLC and suggest the protective role of ART towards spatiotemporal alteration of BLC by preventing the structural and molecular change in BLC. Thus, the findings advocate ART as a potential therapeutic drug for diseases associated with reduced catalase activity.


Assuntos
Antioxidantes/química , Artemisininas/química , Catalase/química , Animais , Antioxidantes/metabolismo , Artemisininas/metabolismo , Catalase/isolamento & purificação , Catalase/metabolismo , Domínio Catalítico , Bovinos , Humanos , Ligação de Hidrogênio , Fígado/química , Fígado/enzimologia , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína , Termodinâmica
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