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1.
J Pharm Biomed Anal ; 194: 113806, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33280995

RESUMO

Remdesivir is a prodrug of the nucleotide analogue and used for COVID-19 treatment. However, the bioanalysis of the active metabolites remdesivir nucleotide triphosphate (RTP) and its precursor remdesivir nucleotide monophosphate (RMP) is very challenging. Herein, we established a novel method to separate RTP and RMP on a BioBasic AX column and quantified them by high-performance liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. Stepwise, we optimized chromatographic retention on an anion exchange column, improved stability in matrix through the addition of 5,5'-dithiobis-(2nitrobenzoic acid) and PhosSTOP EASYpack, and increased recovery by dissociation of tight protein binding with 2 % formic acid aqueous solution. The method allowed lower limit of quantification of 20 nM for RMP and 10 nM for RTP. Method validation demonstrated acceptable accuracy (93.6%-103% for RMP, 94.5%-107% for RTP) and precision (RSD < 11.9 % for RMP, RSD < 11.4 % for RTP), suggesting that it was sensitive and robust for simultaneous quantification of RMP and RTP. The method was successfully applied to analyze RMP and RTP in mouse tissues. In general, the developed method is suitable to monitor RMP and RTP, and provides a useful approach for exploring more detailed effects of remdesivir in treating diseases.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Pró-Fármacos/análise , Pró-Fármacos/metabolismo , Espectrometria de Massas em Tandem/métodos , Monofosfato de Adenosina/análise , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/análise , Alanina/metabolismo , Alanina/farmacologia , Animais , Antivirais/análise , Antivirais/metabolismo , Antivirais/farmacologia , /metabolismo , Cromatografia Líquida/métodos , Humanos , Fígado/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Pró-Fármacos/farmacologia
2.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33378565

RESUMO

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Assuntos
/metabolismo , Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , /antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Azóis/administração & dosagem , Azóis/metabolismo , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Naftoquinonas/administração & dosagem , Naftoquinonas/metabolismo , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico
3.
Bioorg Chem ; 106: 104497, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261847

RESUMO

The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential inhibitors of the SARS CoV-2 main protease (3CLpro). The compounds were obtained in good overall yields and molecular docking indicated favorable binding with 3CLpro. In silico ADME/Tox profile of the new compounds were calculated using the SwissADME and pkCSM-pharmacokinetics web tools, and indicated adequate values of absorption, distribution and excretion, features related to bioavailability. Moreover, low values of toxicity were indicated for these compounds. And drug-likeness levels of the compounds were also predicted according to the Lipinski and Veber rules.


Assuntos
Antivirais/metabolismo , Azidas/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Indóis/metabolismo , /química , Antivirais/síntese química , Antivirais/farmacocinética , Azidas/síntese química , Azidas/farmacocinética , Domínio Catalítico , /metabolismo , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Indóis/síntese química , Indóis/farmacocinética , Internet , Simulação de Acoplamento Molecular , Ligação Proteica
4.
Food Chem ; 334: 127508, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32711265

RESUMO

Quercetin, a potential polyphenolic which possesses several biological effects. The influenza virus polymerase basic 2 (PB2) subunit of RNA polymerase responsible for replication, degree of virus conservation and active target site for designing specific antivirals. The quercetin derivatives downloaded from PubChem were screened using PyRX software configured with Vina Wizard, targeted on cap-binding site of the PB2 of influenza viral RNA polymerase. Among the PubChem library (total 97,585,747 compounds), 410 quercetin derivatives were screened using molecular docking (affinity: <-9.0 kcal) for their drug-likeness and in vitro cytopathic effect by Sulforhodamine B (SRB) assay. Among all quercetin derivatives, quercetin 3'-glucuronide (Q3G) showed strongest binding affinity towards cap-binding site of the PB2 subunit with -9.6 kcal of binding affinity and 0.00054 mM of Ki value, while quercetin 3'-glucuronide (Q7G) was presented highest anti-influenza activity with 2.10 ± 0.05 of IC50 on influenza A/PR/8/34 virus and non-cytotoxic effect as CC50 > 100 µg/mL.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Antivirais/química , Antivirais/metabolismo , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/metabolismo , Cães , Humanos , Vírus da Influenza A/enzimologia , Influenzavirus B/efeitos dos fármacos , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Quercetina/química , Quercetina/metabolismo , Quercetina/farmacologia , Termodinâmica
5.
Phys Chem Chem Phys ; 22(48): 28434-28439, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33305304

RESUMO

The sudden arrival of novel coronavirus disease 2019 (COVID-19) has stunned the world with its rapidly spreading virus. Remdesivir, a broad spectrum anti-viral drug, is now under in vitro and in vivo investigation as a potential agent against SARS-CoV-2. However, the results of this therapy were recently equivocal due to no significant benefit in the clinical trial. Herein, combination molecular docking with dissipative particle dynamics (DPD) simulations is used to theoretically design angiotensin-converting enzyme inhibitor (ACEI)-containing remdesivir-loaded PLGA nanoparticles (NPs) for anti-SARS-CoV-2 therapy. Based on the therapeutic and lung protective effect of ACEI, the classical lisinopril molecule covalently grafted onto PLGA (L-PLGA) has been used to encapsulate remdesivir. A binding model is used to confirm the interactions between lisinopril and ACE on the surface of cells, as well as remdesivir and its intracellular targeting protein (RNA-dependent RNA polymerase (RdRp)). Furthermore, DPD simulations are applied to study the nano-aggregation of drug-free L-PLGA, and remdesivir loaded in L-PLGA. The lisinopril molecules were directly demonstrated to be on the surface of L-PLGA NPs. Molecular docking proved that hydrogen bonding was decisive for the encapsulation of remdesivir. With an increase in concentration, remdesivir loaded L-PLGA formed spherical NPs, and then underwent precipitation. Similar to the above conditions, high remdesivir loading was also observed to cause precipitation formation. Thus, the optimized remdesivir NPs in our study give insights into a rational platform for formulation design against this global pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Antivirais/metabolismo , Portadores de Fármacos/química , Lisinopril/metabolismo , Nanopartículas/química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Alanina/química , Alanina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Antivirais/química , Sinergismo Farmacológico , Humanos , Lisinopril/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ligação Proteica , /efeitos dos fármacos
6.
Viruses ; 12(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271762

RESUMO

The emergence of SARS-CoV-2 in 2019 has caused a major health and economic crisis around the globe. Gaining knowledge about its attributes and interactions with human host cells is crucial. Non-coding RNAs (ncRNAs) are involved in the host cells' innate antiviral immune response. In RNA interference, microRNAs (miRNAs) may bind to complementary sequences of the viral RNA strand, forming an miRNA-induced silencing complex, which destroys the viral RNA, thereby inhibiting viral protein expression. There are several targets for human miRNAs on SARS-CoV-2's RNA, most of which are in the 5' and 3' untranslated regions. Mutations of the viral genome causing the creation or loss of miRNA binding sites may have crucial effects on SARS-CoV-2 pathogenicity. In addition to mediating immunity, the ncRNA landscape of host cells further influences their susceptibility to virus infection, as certain miRNAs are essential in the regulation of cellular receptors that are necessary for virus invasion. Conversely, virus infection also changes the host ncRNA expression patterns, possibly augmenting conditions for viral replication and dissemination. Hence, ncRNAs typically upregulated in SARS-CoV-2 infection could be useful biomarkers for disease progression and severity. Understanding these mechanisms could provide further insight into the pathogenesis and possible treatment options against COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Coronavirus/patogenicidade , RNA não Traduzido/metabolismo , Animais , Antivirais/metabolismo , Antivirais/uso terapêutico , Coronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Humanos , Evasão da Resposta Imune/genética , Mutação , Interferência de RNA , RNA não Traduzido/genética , RNA não Traduzido/uso terapêutico , RNA Viral/genética
7.
J Phys Chem B ; 124(50): 11337-11348, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33264025

RESUMO

The outbreak of a new coronavirus SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) has caused a global COVID-19 (coronavirus disease 2019) pandemic, resulting in millions of infections and thousands of deaths around the world. There is currently no drug or vaccine for COVID-19, but it has been revealed that some commercially available drugs are promising, at least for treating symptoms. Among them, remdesivir, which can block the activity of RNA-dependent RNA polymerase (RdRp) in old SARS-CoV and MERS-CoV viruses, has been prescribed to COVID-19 patients in many countries. A recent experiment showed that remdesivir binds to SARS-CoV-2 with an inhibition constant of µM, but the exact target has not been reported. In this work, combining molecular docking, steered molecular dynamics, and umbrella sampling, we examined its binding affinity to two targets including the main protease (Mpro), also known as 3C-like protease, and RdRp. We showed that remdesivir binds to Mpro slightly weaker than to RdRp, and the corresponding inhibition constants, consistent with the experiment, fall to the µM range. The binding mechanisms of remdesivir to two targets differ in that the electrostatic interaction is the main force in stabilizing the RdRp-remdesivir complex, while the van der Waals interaction dominates in the Mpro-remdesivir case. Our result indicates that remdesivir can target not only RdRp but also Mpro, which can be invoked to explain why this drug is effective in treating COVID-19. We have identified residues of the target protein that make the most important contribution to binding affinity, and this information is useful for drug development for this disease.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/metabolismo , /metabolismo , /metabolismo , Monofosfato de Adenosina/metabolismo , Alanina/metabolismo , Algoritmos , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , /enzimologia , Eletricidade Estática
8.
Nat Commun ; 11(1): 6182, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273464

RESUMO

Upon sensing cytosolic DNA, the enzyme cGAS induces innate immune responses that underpin anti-microbial defenses and certain autoimmune diseases. Missense mutations of PRKDC encoding the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) are associated with autoimmune diseases, yet how DNA-PK deficiency leads to increased immune responses remains poorly understood. In this study, we report that DNA-PK phosphorylates cGAS and suppresses its enzymatic activity. DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses, thereby potently restricting viral replication. Moreover, cells isolated from DNA-PKcs-deficient mice or patients carrying PRKDC missense mutations exhibit an inflammatory gene expression signature. This study provides a rational explanation for the autoimmunity of patients with missense mutations of PRKDC, and suggests that cGAS-mediated immune signaling is a potential target for therapeutic interventions.


Assuntos
Antivirais/metabolismo , Proteína Quinase Ativada por DNA/deficiência , Imunidade Inata , Nucleotidiltransferases/metabolismo , Animais , Linhagem Celular , Cromonas/farmacologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica/efeitos dos fármacos , RNA Guia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , Simplexvirus/fisiologia , Células THP-1 , Vesiculovirus/efeitos dos fármacos , Vesiculovirus/fisiologia , Replicação Viral/efeitos dos fármacos
9.
Acta Crystallogr C Struct Chem ; 76(Pt 12): 1043-1050, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33273140

RESUMO

The first example of molecular docking of the SARS-CoV-2 main protease for COVID-19 [Mpro, Protein Data Bank (PDB) code 7BQY] by a chalcone-based ligand, namely, (E)-1-(2,4-dichlorophenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one, C19H17Cl2NO2, I, is presented. Two-dimensional (2D) LIGPLOT representations calculated for the inhibitor N3, viz. N-{[(5-methylisoxazol-3-yl)carbonyl]alanyl}-L-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide, and 7BQY are included for comparison with our chalcone-based complexes. The binding affinity of our chalcone ligand with 7BQY is -7.0 kcal mol-1, a high value which was attributed to the presence of a hydrogen bond, together with many hydrophobic interactions between the drug and the active amino acid residues of the receptor. Docking studies were also performed, employing rigid and flexible binding modes for the ligand. The superposition of N3 and the chalcone docked into the binding pocket of 7BQY is also presented. The synthesis, single-crystal structure, Hirshfeld surface analysis (HSA) and spectral characterization of heterocyclic chalcone-based compound I, are also presented. The molecules are stacked, with normal π-π interactions, in the crystal.


Assuntos
Antivirais/metabolismo , Chalconas/metabolismo , /enzimologia , Antivirais/síntese química , Antivirais/química , Domínio Catalítico , Chalconas/síntese química , Chalconas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Oligopeptídeos/metabolismo , Ligação Proteica , Estereoisomerismo
10.
Drug Resist Updat ; 53: 100721, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33132205

RESUMO

Coronaviridae is a peculiar viral family, with a very large RNA genome and characteristic appearance, endowed with remarkable tendency to transfer from animals to humans. Since the beginning of the 21st century, three highly transmissible and pathogenic coronaviruses have crossed the species barrier and caused deadly pneumonia, inflicting severe outbreaks and causing human health emergencies of inconceivable magnitude. Indeed, in the past two decades, two human coronaviruses emerged causing serious respiratory illness: severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV), causing more than 10,000 cumulative cases, with mortality rates of 10 % for SARS-CoV-1 and 34.4 % for MERS-CoV. More recently, the severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) has emerged in China and has been identified as the etiological agent of the recent COVID-19 pandemic outbreak. It has rapidly spread throughout the world, causing nearly 22 million cases and ∼ 770,000 deaths worldwide, with an estimated mortality rate of ∼3.6 %, hence posing serious challenges for adequate and effective prevention and treatment. Currently, with the exception of the nucleotide analogue prodrug remdesivir, and despite several efforts, there is no known specific, proven, pharmacological treatment capable of efficiently and rapidly inducing viral containment and clearance of SARS-CoV-2 infection as well as no broad-spectrum drug for other human pathogenic coronaviruses. Another confounding factor is the paucity of molecular information regarding the tendency of coronaviruses to acquire drug resistance, a gap that should be filled in order to optimize the efficacy of antiviral drugs. In this light, the present review provides a systematic update on the current knowledge of the marked global efforts towards the development of antiviral strategies aimed at coping with the infection sustained by SARS-CoV-2 and other human pathogenic coronaviruses, displaying drug resistance profiles. The attention has been focused on antiviral drugs mainly targeting viral protease, RNA polymerase and spike glycoprotein, that have been tested in vitro and/or in clinical trials as well as on promising compounds proven to be active against coronaviruses by an in silico drug repurposing approach. In this respect, novel insights on compounds, identified by structure-based virtual screening on the DrugBank database endowed by multi-targeting profile, are also reported. We specifically identified 14 promising compounds characterized by a good in silico binding affinity towards, at least, two of the four studied targets (viral and host proteins). Among which, ceftolozane and NADH showed the best multi-targeting profile, thus potentially reducing the emergence of resistant virus strains. We also focused on potentially novel pharmacological targets for the development of compounds with anti-pan coronavirus activity. Through the analysis of a large set of viral genomic sequences, the current review provides a comprehensive and specific map of conserved regions across human coronavirus proteins which are essential for virus replication and thus with no or very limited tendency to mutate. Hence, these represent key druggable targets for novel compounds against this virus family. In this respect, the identification of highly effective and innovative pharmacological strategies is of paramount importance for the treatment and/or prophylaxis of the current pandemic but potentially also for future and unavoidable outbreaks of human pathogenic coronaviruses.


Assuntos
Antivirais/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , /efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antivirais/química , Antivirais/metabolismo , /metabolismo , Infecções por Coronavirus/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Humanos , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , /metabolismo
11.
Bioorg Chem ; 104: 104326, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33142431

RESUMO

SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.


Assuntos
Antivirais/metabolismo , Vírus da SARS/química , Proteínas não Estruturais Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Sequência de Aminoácidos , Animais , Antivirais/uso terapêutico , Sítios de Ligação , /epidemiologia , Reposicionamento de Medicamentos , Humanos , Ligação Proteica , Proteínas não Estruturais Virais/química , Proteínas Estruturais Virais/química
12.
Drug Resist Updat ; 53: 100733, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33161277

RESUMO

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented challenge to global public health. At the time of this review, COVID-19 has been diagnosed in over 40 million cases and associated with 1.1 million deaths worldwide. Current management strategies for COVID-19 are largely supportive, and while there are more than 2000 interventional clinical trials registered with the U.S. National Library of Medicine (clinicaltrials.gov), results that can clarify benefits and risks of candidate therapies are only gradually becoming available. We herein describe recent advances in understanding SARS-CoV-2 pathobiology and potential therapeutic targets that are involved in viral entry into host cells, viral spread in the body, and the subsequent COVID-19 progression. We highlight two major lines of therapeutic strategies for COVID-19 treatment: 1) repurposing the existing drugs for use in COVID-19 patients, such as antiviral medications (e.g., remdesivir) and immunomodulators (e.g., dexamethasone) which were previously approved for other disease conditions, and 2) novel biological products that are designed to target specific molecules that are involved in SARS-CoV-2 viral entry, including neutralizing antibodies against the spike protein of SARS-CoV-2, such as REGN-COV2 (an antibody cocktail), as well as recombinant human soluble ACE2 protein to counteract SARS-CoV-2 binding to the transmembrane ACE2 receptor in target cells. Finally, we discuss potential drug resistance mechanisms and provide thoughts regarding clinical trial design to address the diversity in COVID-19 clinical manifestation. Of note, preventive vaccines, cell and gene therapies are not within the scope of the current review.


Assuntos
Antivirais/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antivirais/imunologia , Antivirais/metabolismo , /metabolismo , Desenvolvimento de Medicamentos/tendências , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Fatores de Tempo , Internalização do Vírus/efeitos dos fármacos
13.
Chem Biol Interact ; 332: 109309, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181114

RESUMO

In the present situation, COVID-19 has become the global health concern due to its high contagious nature. It initially appeared in December 2019 in Wuhan, China and now affected more than 190 countries. As of now preventive measures are the sole solution to stop this disease for further transmission from person to person transmissions as there is no effective treatment or vaccine available to date. Research and development of new molecule is a laborious process; therefore, drug repurposing can be an alternative solution that involves the identification of potential compounds from the already available data. Alkaloids are potential source of therapeutic agents which might be able to treat novel COVID-19. Therefore, in the present study, twenty potential alkaloid molecules that possess antiviral activity against different viral diseases have taken into consideration and scrutinized using Lipinski's rule. Then out of twenty compounds seventeen were further selected for docking study. Docking study was performed using Autodock software and the best four molecule which provides maximum negative binding energy was selected for further analysis. Two alkaloids namely thalimonine and sophaline D showed potential activity to inhibit the Mpro but to confirm the claim further in-vitro studies are required.


Assuntos
Alcaloides/metabolismo , Antivirais/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , /enzimologia , Alcaloides/química , Antivirais/química , Domínio Catalítico , /metabolismo , Inibidores de Cisteína Proteinase/química , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Estrutura Secundária de Proteína/efeitos dos fármacos
14.
Protein J ; 39(6): 619-630, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33185784

RESUMO

Remdesivir was approved by the U.S.A. Food and Drug administration for emergency use to interfere with the replication of SARS CoV-2 virus (the agent that causes COVID-19) in adults and children hospitalized with severe disease. The crystal structure of the metabolite of remdesivir (Monophosphate of GS-441524) and NSP12-NSP8-NSP7 of SARS CoV-2 virus was recently reported. The crystal structures of ADP-Ribose or AMP and NSP3 of SARS CoV-2 virus were also released, recently. This study compared their binding sites and suggests the crystal structure of NSP3 of SARS CoV-2 virus as an alternative binding site of AMP or ADP-ribose to treat COVID-19. We virtually screened 682 FDA-approved compounds, and the top 10 compounds were selected by analysis of docking scores, (G-score, D-score, and Chemscore) and visual analysis using a structure-based docking approach of NSP3 of SARS CoV-2 virus. All immunization approaches are based on the SARS-CoV-2 virus spike protein. A recent study reported that the D614G mutation in the SARS-CoV-2 virus spike protein reduces S1 shedding and increases infectivity of SARS COV-2 virus. Therefore, if there is a severe change in the spike protein of a modified Coronavirus, all developed vaccines can lose their efficacy, necessitating the need for an alternative treatment method. The top 10 compounds (FDA-approved) in this study are selected based on NSP 3 binding site, and therefore are a potential viable treatment because they will show potential activity for all mutations in the SARS-CoV-2 virus spike protein.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , /efeitos dos fármacos , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/química , Alanina/metabolismo , Alanina/farmacologia , Antivirais/química , Antivirais/metabolismo , Sítios de Ligação , /virologia , /metabolismo , /metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica/efeitos dos fármacos , /metabolismo
15.
Adv Drug Deliv Rev ; 167: 47-65, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189768

RESUMO

To date, no effective vaccines or therapies are available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pandemic agent of the coronavirus disease 2019 (COVID-19). Due to their safety, efficacy and specificity, peptide inhibitors hold great promise for the treatment of newly emerging viral pathogens. Based on the known structures of viral proteins and their cellular targets, antiviral peptides can be rationally designed and optimized. The resulting peptides may be highly specific for their respective targets and particular viral pathogens or exert broad antiviral activity. Here, we summarize the current status of peptides inhibiting SARS-CoV-2 entry and outline the strategies used to design peptides targeting the ACE2 receptor or the viral spike protein and its activating proteases furin, transmembrane serine protease 2 (TMPRSS2), or cathepsin L. In addition, we present approaches used against related viruses such as SARS-CoV-1 that might be implemented for inhibition of SARS-CoV-2 infection.


Assuntos
Antivirais/administração & dosagem , /metabolismo , Fragmentos de Peptídeos/administração & dosagem , /metabolismo , Sequência de Aminoácidos , /metabolismo , Antivirais/química , Antivirais/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/metabolismo
16.
J Mol Model ; 26(12): 341, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33200284

RESUMO

HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of - 9.42, - 8.93, - 8.45 and - 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic.


Assuntos
Antineoplásicos/química , Antivirais/química , Betacoronavirus/química , Elétrons , Oxazóis/química , Inibidores de Proteases/química , Piridinas/química , Quinazolinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antineoplásicos/metabolismo , Antivirais/metabolismo , Betacoronavirus/enzimologia , Sítios de Ligação , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazóis/metabolismo , Inibidores de Proteases/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Piridinas/metabolismo , Teoria Quântica , Quinazolinas/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
17.
J Phys Chem B ; 124(48): 10930-10942, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33200935

RESUMO

SARS-CoV-2 is the novel coronavirus causing the COVID-19 pandemic. To enter human cells, the receptor-binding domain (RBD) of the S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) initially binds to the peptidase domain of angiotensin-converting enzyme 2 receptor (ACE2-PD). Using peptides to inhibit SARS-CoV-2-RBD binding to ACE2 is a potential therapeutic solution for COVID-19. A previous study identified a 23-mer peptide (SBP1) that bound to SARS-CoV-2-RBD with comparable KD to ACE2. We employed computational protein design and molecular dynamics (MD) to design SARS-CoV-2-RBD 25-mer peptide binders (SPB25) with better predicted binding affinity than SBP1. Using residues 21-45 of the α1 helix of ACE2-PD as the template, our strategy is employing Rosetta to enhance SPB25 binding affinity to SARS-CoV-2-RBD and avoid disrupting existing favorable interactions by using residues that have not been reported to form favorable interactions with SARS-CoV-2-RBD as designed positions. Designed peptides with better predicted binding affinities, by Rosetta, than SPB25 were subjected to MD validation. The MD results show that five designed peptides (SPB25F8N, SPB25F8R, SPB25L25R, SPB25F8N/L25R, and SPB25F8R/L25R) have better predicted binding affinities, by the MM-GBSA method, than SPB25 and SBP1. This study developed an approach to design SARS-CoV-2-RBD peptide binders, and these peptides may be promising candidates as potential SARS-CoV-2 inhibitors.


Assuntos
Antivirais/metabolismo , Peptídeos/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Antivirais/química , Sítios de Ligação , Desenho de Fármacos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Eletricidade Estática , Termodinâmica
18.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33140636

RESUMO

Cell entry, the fundamental step in cross-species transmission of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is initiated by the recognition of the host cell angiotensin-converting enzyme-2 (ACE2) receptor by the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. To date, several peptides have been proposed against SARS-CoV-2 both as inhibitor agents or as detection tools that can also be attached to the surfaces of nanoparticle carriers. But owing to their natural amino acid sequences, such peptides cannot be considered as efficient therapeutic candidates from a biostability point of view. This discussion demonstrates the design strategy of synthetic nonprotein amino acid substituted peptides with enhanced biostability and binding affinity, the implication of which can make those peptides potential therapeutic agents for inhibition and simple detection tools.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Sequência de Aminoácidos , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Ligação Proteica/fisiologia , Análise de Sequência de Proteína/métodos
19.
J Phys Chem B ; 124(47): 10641-10652, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33190493

RESUMO

Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (-59.6 kcal/mol) binds more strongly as compared to compound-8 (-46.3 kcal/mol) and remdesivir (-29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/metabolismo , Inibidores Enzimáticos/metabolismo , /enzimologia , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/toxicidade , Alanina/química , Alanina/metabolismo , Alanina/farmacocinética , Alanina/toxicidade , Antivirais/química , Antivirais/farmacocinética , Antivirais/toxicidade , Células CACO-2 , Domínio Catalítico , /metabolismo , Teoria da Densidade Funcional , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Humanos , Ligação de Hidrogênio , Modelos Químicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Termodinâmica
20.
Nucleic Acids Res ; 48(22): 12436-12452, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33166999

RESUMO

SARS-CoV-2 is a betacoronavirus with a linear single-stranded, positive-sense RNA genome, whose outbreak caused the ongoing COVID-19 pandemic. The ability of coronaviruses to rapidly evolve, adapt, and cross species barriers makes the development of effective and durable therapeutic strategies a challenging and urgent need. As for other RNA viruses, genomic RNA structures are expected to play crucial roles in several steps of the coronavirus replication cycle. Despite this, only a handful of functionally-conserved coronavirus structural RNA elements have been identified to date. Here, we performed RNA structure probing to obtain single-base resolution secondary structure maps of the full SARS-CoV-2 coronavirus genome both in vitro and in living infected cells. Probing data recapitulate the previously described coronavirus RNA elements (5' UTR and s2m), and reveal new structures. Of these, ∼10.2% show significant covariation among SARS-CoV-2 and other coronaviruses, hinting at their functionally-conserved role. Secondary structure-restrained 3D modeling of these segments further allowed for the identification of putative druggable pockets. In addition, we identify a set of single-stranded segments in vivo, showing high sequence conservation, suitable for the development of antisense oligonucleotide therapeutics. Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-related infections.


Assuntos
/prevenção & controle , Genoma Viral/genética , Conformação de Ácido Nucleico , RNA Viral/química , /genética , Regiões 5' não Traduzidas/genética , Algoritmos , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sequência de Bases , Sítios de Ligação/genética , /virologia , Sequência Conservada/genética , Humanos , Modelos Moleculares , Pandemias , /fisiologia
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