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1.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Nat Commun ; 11(1): 4371, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873790

RESUMO

Pentacyclic triterpenoids (PTs) constitute one of the biggest families of natural products, many with higher oxidation state at the D/E rings possess a wide spectrum of biological activties but are poorly accessible. Here we report a site-selective C-H hydroxylation at the D/E rings of PTs paving a way toward these important natural products. We find that Schönecker and Baran's Cu-mediated aerobic oxidation can be applied and become site-selective on PT skeletons, as being effected unexpectedly by the chirality of the transient pyridine-imino directing groups. To prove the applicability, starting from the most abundant triterpenoid feedstock oleanane, three representative saponins bearing hydroxyl groups at C16 or C22 are expeditiously synthesized, and barringtogenol C which bears hydroxyl groups at C16, C21, and C22 is synthesized via a sequential hydroxylation as the key steps.


Assuntos
Produtos Biológicos/química , Técnicas de Química Sintética , Triterpenos Pentacíclicos/química , Química Farmacêutica , Hidroxilação , Relação Estrutura-Atividade
3.
Molecules ; 25(18)2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899754

RESUMO

The emergence of the Coronavirus Disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has led to an unprecedented pandemic, which demands urgent development of antiviral drugs and antibodies; as well as prophylactic approaches, namely vaccines. Algae biotechnology has much to offer in this scenario given the diversity of such organisms, which are a valuable source of antiviral and anti-inflammatory compounds that can also be used to produce vaccines and antibodies. Antivirals with possible activity against SARS-CoV-2 are summarized, based on previously reported activity against Coronaviruses or other enveloped or respiratory viruses. Moreover, the potential of algae-derived anti-inflammatory compounds to treat severe cases of COVID-19 is contemplated. The scenario of producing biopharmaceuticals in recombinant algae is presented and the cases of algae-made vaccines targeting viral diseases is highlighted as valuable references for the development of anti-SARS-CoV-2 vaccines. Successful cases in the production of functional antibodies are described. Perspectives on how specific algae species and genetic engineering techniques can be applied for the production of anti-viral compounds antibodies and vaccines against SARS-CoV-2 are provided.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Chlamydomonas reinhardtii/genética , Infecções por Coronavirus/tratamento farmacológico , Lectinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Polifenóis/farmacologia , Polissacarídeos/farmacologia , Antivirais/química , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Núcleo Celular/química , Núcleo Celular/genética , Núcleo Celular/metabolismo , Chlamydomonas reinhardtii/química , Chlamydomonas reinhardtii/metabolismo , Cloroplastos/química , Cloroplastos/genética , Cloroplastos/metabolismo , Infecções por Coronavirus/prevenção & controle , Engenharia Genética/métodos , Humanos , Lectinas/química , Lectinas/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Polifenóis/química , Polifenóis/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vacinas Virais/biossíntese , Vacinas Virais/farmacologia
4.
Molecules ; 25(17)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882868

RESUMO

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Produtos Biológicos/farmacologia , Infecções por Coronavirus/virologia , Flavonoides/farmacologia , Pneumonia Viral/virologia , Inibidores da Enzima Conversora de Angiotensina/química , Antivirais/química , Produtos Biológicos/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Suscetibilidade a Doenças , Flavonoides/química , Humanos , Estágios do Ciclo de Vida , Modelos Moleculares , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Vigilância da População , Relação Estrutura-Atividade
5.
Nat Commun ; 11(1): 4372, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873801

RESUMO

3D molecular structure determination is a challenge for organic compounds or natural products available in minute amounts. Proton/proton and proton/carbon correlations yield the constitution. J couplings and NOEs oftentimes supported by one-bond 1H,13C residual dipolar couplings (RDCs) or by 13C residual chemical shift anisotropies (RCSAs) provide the relative configuration. However, these RDCs or carbon RCSAs rely on 1% natural abundance of 13C preventing their use for compounds available only in quantities of a few 10's of µgs. By contrast, 1H RCSAs provide similar information on spatial orientation of structural moieties within a molecule, while using the abundant 1H spin. Herein, 1H RCSAs are accurately measured using constrained aligning gels or liquid crystals and applied to the 3D structural determination of molecules with varying complexities. Even more, deuterated alignment media allow the elucidation of the relative configuration of around 35 µg of a briarane compound isolated from Briareum asbestinum.


Assuntos
Antozoários/química , Produtos Biológicos/química , Diterpenos/química , Conformação Molecular , Prótons , Animais , Anisotropia , Espectroscopia de Prótons por Ressonância Magnética
6.
Mar Drugs ; 18(10)2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993146

RESUMO

For a long time, algal chemistry from terrestrial to marine or freshwater bodies, especially chlorophytes, has fascinated numerous investigators to develop new drugs in the nutraceutical and pharmaceutical industries. As such, chlorophytes comprise a diverse structural class of secondary metabolites, having functional groups that are specific to a particular source. All bioactive compounds of chlorophyte are of great interest due to their supplemental/nutritional/pharmacological activities. In this review, a detailed description of the chemical diversity of compounds encompassing alkaloids, terpenes, steroids, fatty acids and glycerides, their subclasses and their structures are discussed. These promising natural products have efficiency in developing new drugs necessary in the treatment of various deadly pathologies (cancer, HIV, SARS-CoV-2, several inflammations, etc.). Marine chlorophyte, therefore, is portrayed as a pivotal treasure in the case of drugs having marine provenience. It is a domain of research expected to probe novel pharmaceutically or nutraceutically important secondary metabolites resulting from marine Chlorophyta. In this regard, our review aims to compile the isolated secondary metabolites having diverse chemical structures from chlorophytes (like Caulerpa ssp., Ulva ssp., Tydemania ssp., Penicillus ssp., Codium ssp., Capsosiphon ssp., Avrainvillea ssp.), their biological properties, applications and possible mode of action.


Assuntos
Produtos Biológicos/farmacologia , Clorófitas/química , Clorófitas/metabolismo , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Produtos Biológicos/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Neoplasias/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
7.
Nature ; 584(7819): 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760044

RESUMO

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.


Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/química
8.
J Chromatogr A ; 1626: 461368, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797847

RESUMO

Recycling counter-current chromatography (CCC) has been developed and widely used in preparative separation. Due to increasingly broader peaks with longer elution times, recycling elution must be stopped before a peak overlap occurs, resulting in the insufficient separation of target compounds. In this study, the concept of in situ concentration was proposed, and the corresponding technique was designed to compress the effluents with the reserved separation effect (peak resolution). By combining this technique with multi-stage recycling elution, a novel unlimited recycling CCC (URCCC) strategy was developed to overcome the recycling time limitation to improve the resolution. The URCCC strategy was successfully applied in the preparative separation of naturally occurring naphthaquinones, where the in situ concentration was used two times with three-stage recycling CCC elution. Finally, isobutyrylshikonin (1), ß, ß-dimethylacrylshikonin (2) and isovalerylshikonin (3) were separated with high resolutions (R1,2 = 1.38 and R2,3 = 1.26). A high yield of pure naphthaquinones was achieved (89.6%), and the purity of each exceeded 98%. In conclusion, the URCCC strategy can improve the recycling elution times until the target compounds achieve sufficient separation, which may enable a broader range of application in structurally related compounds separation, especially in natural product separation.


Assuntos
Produtos Biológicos/química , Distribuição Contracorrente , Naftoquinonas/isolamento & purificação , Ácidos Pentanoicos/isolamento & purificação
9.
Nat Commun ; 11(1): 4022, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782248

RESUMO

One major bottleneck in natural product drug development is derivatization, which is pivotal for fine tuning lead compounds. A promising solution is modifying the biosynthetic machineries of middle molecules such as macrolides. Although intense studies have established various methodologies for protein engineering of type I modular polyketide synthase(s) (PKSs), the accurate targeting of desired regions in the PKS gene is still challenging due to the high sequence similarity between its modules. Here, we report an innovative technique that adapts in vitro Cas9 reaction and Gibson assembly to edit a target region of the type I modular PKS gene. Proof-of-concept experiments using rapamycin PKS as a template show that heterologous expression of edited biosynthetic gene clusters produced almost all the desired derivatives. Our results are consistent with the promiscuity of modular PKS and thus, our technique will provide a platform to generate rationally designed natural product derivatives for future drug development.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Policetídeo Sintases/genética , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Estrutura Molecular , Família Multigênica/genética , Policetídeo Sintases/metabolismo , Sirolimo/química , Sirolimo/metabolismo , Estereoisomerismo , Streptomyces/enzimologia , Streptomyces/genética , Streptomyces/metabolismo
10.
Nat Commun ; 11(1): 4170, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820174

RESUMO

Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


Assuntos
Dissulfetos/química , Indicadores e Reagentes/química , Peptídeos/química , Sulfetos/química , Enxofre/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Indicadores e Reagentes/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/química
11.
J Chromatogr A ; 1625: 461272, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709324

RESUMO

Trapping multiple dual mode (trapping MDM) is a preparative liquid-liquid chromatography (LLC) technique well-suited to difficult separations of intermediately-eluting components from similarly structured impurities. In this demonstrative study, a design approach for high process throughput is applied for the trapping MDM separation of a target component, nootkatone (NK), initially comprising 16.7% of an industrial side stream mixture with over 90 impurities. This design approach, previously developed and validated using ternary mixtures of model solutes, is applied to a complex real mixture for the first time. The approach consists of five steps: (1) determination of the maximum starting mixture concentration for feed preparation; (2) determination of the maximum flow rate for maintenance of the pre-set stationary phase fraction; (3) determination of the partition coefficients of the target and main impurities; (4) selection of step durations and number of cycles using an established short-cut method; (5) execution of the trapping MDM separation. The target, NK, was obtained along with a co-eluting component at 78.7% purity and 84.6% yield, demonstrating the effectiveness of trapping MDM for the separation of intermediately-eluting natural product target components from complex starting mixtures.


Assuntos
Produtos Biológicos/química , Cromatografia Líquida/métodos , Extratos Vegetais/química , Sesquiterpenos Policíclicos/isolamento & purificação , Distribuição Contracorrente , Cromatografia Gasosa-Espectrometria de Massas , Sesquiterpenos Policíclicos/química , Reologia , Soluções , Solventes/química
12.
Biomolecules ; 10(7)2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645994

RESUMO

Oceans cover more than 70 percent of the surface of our planet and are characterized by huge taxonomic and chemical diversity of marine organisms. Several studies have shown that marine organisms produce a variety of compounds, derived from primary or secondary metabolism, which may have antiviral activities. In particular, certain marine metabolites are active towards a plethora of viruses. Multiple mechanisms of action have been found, as well as different targets. This review gives an overview of the marine-derived compounds discovered in the last 10 years. Even if marine organisms produce a wide variety of different compounds, there is only one compound available on the market, Ara-A, and only another one is in phase I clinical trials, named Griffithsin. The recent pandemic emergency caused by SARS-CoV-2, also known as COVID-19, highlights the need to further invest in this field, in order to shed light on marine compound potentiality and discover new drugs from the sea.


Assuntos
Antivirais/química , Organismos Aquáticos/química , Produtos Biológicos/química , Antivirais/farmacologia , Organismos Aquáticos/classificação , Produtos Biológicos/farmacologia , Coronaviridae/efeitos dos fármacos
13.
Nat Commun ; 11(1): 3337, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620756

RESUMO

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L-1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.


Assuntos
Alcaloides/biossíntese , Benzilisoquinolinas/metabolismo , Saccharomyces cerevisiae/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Alcaloides/química , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Benzilisoquinolinas/química , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Engenharia Genética , Modelos Químicos , Estrutura Molecular , Saccharomyces cerevisiae/genética , Tetra-Hidroisoquinolinas/química
14.
Interdiscip Sci ; 12(3): 335-348, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32617855

RESUMO

Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel drugs from Northern South African medicinal compounds database (NANPDB) by using computational virtual screening and molecular docking approaches. Considering Remdesivir as the control, 42 compounds were shortlisted to have docking score better than Remdesivir. The top 5 hits were validated by using molecular dynamics simulation approach and free energy calculations possess strong inhibitory properties than the Remdesivir. Thus, this study paved a way for designing novel drugs by decoding the architecture of an important enzyme and its inhibition with compounds from natural resources. This disclosing of necessary knowledge regarding the screening and the identification of top hits could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Produtos Biológicos/farmacologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Antivirais/química , Betacoronavirus/genética , Produtos Biológicos/química , Domínio Catalítico/genética , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Bases de Dados de Produtos Farmacêuticos , Avaliação Pré-Clínica de Medicamentos , Genoma Viral , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Pandemias , Filogenia , Pneumonia Viral/epidemiologia , RNA Replicase/química , RNA Replicase/genética , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética
15.
J Nat Med ; 74(4): 741-749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32601830

RESUMO

Cancer cachexia is a complex and multifactorial syndrome that influences about 50-80% of cancer patients and may lead to 20% of cancer deaths and muscle atrophy is the key characteristic of the syndrome. Recent researches have shown that myostatin is a negative regulator in the growth and differentiation of skeletal muscle. Herein, C2C12 cancer cachexia model was established with C26 conditioned culture medium (CCM), then treated with magnolol to evaluate the pharmacological activity of magnolol in myotube atrophy. Our results demonstrated that magnolol inhibited the activity of myostatin promotor and the myostatin signaling pathway. In C2C12 cancer cachexia model, magnolol decreased myostatin expression, inhibited the phosphorylation of SMAD2/3 activated by C26 conditioned culture medium (CCM), and elevated the phosphorylation of FOXO3a lowered by CCM. Myosin heavy chain (MyHC), myogenin (MyoG), and myogenic differentiation (MyoD), as three common myotube markers in C2C12 myotube, were decreased by CCM, which could be effectively reversed by magnolol via activation of AKT/mTOR-regulated protein synthesis and inhibition of ubiquitin-mediated proteolysis. This study reveals that magnolol inhibits myotube atrophy induced by CCM by increasing protein synthesis and decreasing ubiquitin-mediated proteolysis, so that magnolol is a promising leading compound in treating muscle atrophy induced by cancer cachexia.


Assuntos
Anti-Inflamatórios não Esteroides/química , Produtos Biológicos/química , Compostos de Bifenilo/química , Caquexia/tratamento farmacológico , Lignanas/química , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Miostatina/metabolismo , Neoplasias/complicações , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Transfecção
16.
Biochem Pharmacol ; 178: 114123, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593613

RESUMO

Commonly used drugs for treating many conditions are either natural products or derivatives. In silico modelling has identified several natural products including quercetin as potential highly effective disruptors of the initial infection process involving binding to the interface between the SARS-CoV-2 (Covid-19) Viral Spike Protein and the epithelial cell Angiotensin Converting Enzyme-2 (ACE2) protein. Here we argue that the oral route of administration of quercetin is unlikely to be effective in clinical trials owing to biotransformation during digestion, absorption and metabolism, but suggest that agents could be administered directly by alternative routes such as a nasal or throat spray.


Assuntos
Betacoronavirus/efeitos dos fármacos , Produtos Biológicos/farmacologia , Peptidil Dipeptidase A/metabolismo , Quercetina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Estrutura Molecular , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Quercetina/administração & dosagem , Quercetina/química , Internalização do Vírus/efeitos dos fármacos
17.
Eur J Protistol ; 75: 125720, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32569992

RESUMO

For hundreds of years, mankind has benefited from the natural metabolic processes of microorganisms to obtain basic products such as fermented foods and alcoholic beverages. More recently, microorganisms have been exploited for the production of antibiotics, vitamins and enzymes to be used in medicine and chemical industries. Additionally, several modern drugs, including those for cancer therapy, are natural products or their derivatives. Protists are a still underexplored source of natural products potentially of interest for biotechnological and biomedical applications. This paper focuses on some examples of bioactive molecules from protists and associated bacteria and their possible use in biotechnology.


Assuntos
Produtos Biológicos/química , Biotecnologia/tendências , Eucariotos/química , Animais
18.
Nat Commun ; 11(1): 3080, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555154

RESUMO

The exact chemical structure of non-crystallising natural products is still one of the main challenges in Natural Sciences. Despite tremendous advances in total synthesis, the absolute structural determination of a myriad of natural products with very sensitive chemical functionalities remains undone. Here, we show that a metal-organic framework (MOF) with alcohol-containing arms and adsorbed water, enables selective hydrolysis of glycosyl bonds, supramolecular order with the so-formed chiral fragments and absolute determination of the organic structure by single-crystal X-ray crystallography in a single operation. This combined strategy based on a biomimetic, cheap, robust and multigram available solid catalyst opens the door to determine the absolute configuration of ketal compounds regardless degradation sensitiveness, and also to design extremely-mild metal-free solid-catalysed processes without formal acid protons.


Assuntos
Produtos Biológicos/química , Hidrolases/química , Estruturas Metalorgânicas/química , Adsorção , Álcoois/química , Catálise , Cristalografia por Raios X , Glicólise , Hidrólise , Cinética , Metais , Conformação Molecular , Estrutura Molecular , Porosidade , Relação Estrutura-Atividade , Difração de Raios X
19.
Science ; 368(6494): 1007-1011, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32467391

RESUMO

Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.


Assuntos
Produtos Biológicos/síntese química , Briostatinas/síntese química , Macrolídeos/síntese química , Alquinos/química , Produtos Biológicos/química , Briostatinas/química , Técnicas de Química Sintética , Macrolídeos/química
20.
Nat Commun ; 11(1): 2258, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382158

RESUMO

En route to a bio-based chemical industry, the conversion of fatty acids into building blocks is of particular interest. Enzymatic routes, occurring under mild conditions and excelling by intrinsic selectivity, are particularly attractive. Here we report photoenzymatic cascade reactions to transform unsaturated fatty acids into enantiomerically pure secondary fatty alcohols. In a first step the C=C-double bond is stereoselectively hydrated using oleate hydratases from Lactobacillus reuteri or Stenotrophomonas maltophilia. Also, dihydroxylation mediated by the 5,8-diol synthase from Aspergillus nidulans is demonstrated. The second step comprises decarboxylation of the intermediate hydroxy acids by the photoactivated decarboxylase from Chlorella variabilis NC64A. A broad range of (poly)unsaturated fatty acids can be transformed into enantiomerically pure fatty alcohols in a simple one-pot approach.


Assuntos
Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Álcoois Graxos/química , Álcoois Graxos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Lactobacillus reuteri/metabolismo , Stenotrophomonas maltophilia/metabolismo , Especificidade por Substrato
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