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3.
BMC Bioinformatics ; 22(1): 418, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479477

RESUMO

BACKGROUND: Prediction of the drug-target interaction (DTI) is a critical step in the drug repurposing process, which can effectively reduce the following workload for experimental verification of potential drugs' properties. In recent studies, many machine-learning-based methods have been proposed to discover unknown interactions between drugs and protein targets. A recent trend is to use graph-based machine learning, e.g., graph embedding to extract features from drug-target networks and then predict new drug-target interactions. However, most of the graph embedding methods are not specifically designed for DTI predictions; thus, it is difficult for these methods to fully utilize the heterogeneous information of drugs and targets (e.g., the respective vertex features of drugs and targets and path-based interactive features between drugs and targets). RESULTS: We propose a DTI prediction method DTI-HeNE (DTI based on Heterogeneous Network Embedding), which is specifically designed to cope with the bipartite DTI relations for generating high-quality embeddings of drug-target pairs. This method splits a heterogeneous DTI network into a bipartite DTI network, multiple drug homogeneous networks and target homogeneous networks, and extracts features from these sub-networks separately to better utilize the characteristics of bipartite DTI relations as well as the auxiliary similarity information related to drugs and targets. The features extracted from each sub-network are integrated using pathway information between these sub-networks to acquire new features, i.e., embedding vectors of drug-target pairs. Finally, these features are fed into a random forest (RF) model to predict novel DTIs. CONCLUSIONS: Our experimental results show that, the proposed DTI network embedding method can learn higher-quality features of heterogeneous drug-target interaction networks for novel DTIs discovery.


Assuntos
Desenvolvimento de Medicamentos , Preparações Farmacêuticas , Interações Medicamentosas , Reposicionamento de Medicamentos , Aprendizado de Máquina
4.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445599

RESUMO

Not long ago, self-reactive immune activity was considered as pathological trait. A paradigm shift has now led to the recognition of autoimmune processes as part of natural maintenance of molecular homeostasis. The immune system is assigned further roles beneath the defense against pathogenic organisms. Regarding the humoral immune system, the investigation of natural autoantibodies that are frequently found in healthy individuals has led to further hypotheses involving natural autoimmunity in other processes as the clearing of cellular debris or decrease in inflammatory processes. However, their role and origin have not been entirely clarified, but accumulating evidence links their formation to immune reactions against the gut microbiome. Antibodies targeting highly conserved proteins of the commensal microflora are suggested to show self-reactive properties, following the paradigm of the molecular mimicry. Here, we discuss recent findings, which demonstrate potential links of the commensal microflora to the immunological homeostasis and highlight the possible implications for various diseases. Furthermore, specific components of the immune system, especially antibodies, have become a focus of attention for the medical management of various diseases and provide attractive treatment options in the future. Nevertheless, the development and optimization of such macromolecules still represents a very time-consuming task, shifting the need to more medical agents with simple structural properties and low manufacturing costs. Synthesizing only the biologically active sites of antibodies has become of great interest for the pharmaceutical industry and offers a wide range of therapeutic application areas as it will be discussed in the present review article.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Desenvolvimento de Medicamentos , Microbioma Gastrointestinal , Homeostase , Sistema Imunitário/imunologia , Inflamação/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Autoimunidade , Humanos , Sistema Imunitário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia
5.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445426

RESUMO

The causative agent of white tail disease (WTD) in the giant freshwater prawn is Macrobrachium rosenbergii nodavirus (MrNV). The recombinant capsid protein (CP) of MrNV was previously expressed in Escherichia coli, and it self-assembled into icosahedral virus-like particles (VLPs) with a diameter of approximately 30 nm. Extensive studies on the MrNV CP VLPs have attracted widespread attention in their potential applications as biological nano-containers for targeted drug delivery and antigen display scaffolds for vaccine developments. Despite their advantageous features, the recombinant MrNV CP VLPs produced in E. coli are seriously affected by protease degradations, which significantly affect the yield and stability of the VLPs. Therefore, the aim of this study is to enhance the stability of MrNV CP by modulating the protease degradation activity. Edman degradation amino acid sequencing revealed that the proteolytic cleavage occurred at arginine 26 of the MrNV CP. The potential proteases responsible for the degradation were predicted in silico using the Peptidecutter, Expasy. To circumvent proteolysis, specific protease inhibitors (PMSF, AEBSF and E-64) were tested to reduce the degradation rates. Modulation of proteolytic activity demonstrated that a cysteine protease was responsible for the MrNV CP degradation. The addition of E-64, a cysteine protease inhibitor, remarkably improved the yield of MrNV CP by 2.3-fold compared to the control. This innovative approach generates an economical method to improve the scalability of MrNV CP VLPs using individual protease inhibitors, enabling the protein to retain their structural integrity and stability for prominent downstream applications including drug delivery and vaccine development.


Assuntos
Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Cisteína Proteases/metabolismo , Nodaviridae/metabolismo , Palaemonidae/virologia , Animais , Sítios de Ligação , Proteínas do Capsídeo/química , Simulação por Computador , Desenvolvimento de Medicamentos , Regulação Viral da Expressão Gênica , Inibidores de Proteases/farmacologia , Proteólise/efeitos dos fármacos , Análise de Sequência de Proteína
6.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443621

RESUMO

There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.


Assuntos
Desenvolvimento de Medicamentos , Inibidores Enzimáticos/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Animais , Disponibilidade Biológica , Gatos , Cães , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/química , Cavalos , Camundongos , Solubilidade , Especificidade da Espécie
8.
Molecules ; 26(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34361615

RESUMO

In cell development, the cell cycle is crucial, and the cycle progression's main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy's effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Feminino , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
9.
ACS Appl Mater Interfaces ; 13(33): 39100-39111, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34382406

RESUMO

In this work, a nanoplatform (FeCORM NPs) loaded with an iron-carbonyl complex was constructed. By exploiting chemodynamic therapy (CDT) and immunogenic cell death (ICD)-induced immunotherapy (IMT), the nanoparticles exhibited excellent efficacy against lung metastasis of melanoma in vivo. The iron-carbonyl compound of the nanomaterials could be initiated by both glutathione (GSH) and hydrogen peroxide (H2O2) to release CO and generate ferrous iron through ligand exchange and oxidative destruction pathways. The released CO caused mitochondria damage, whereas the generated ferrous iron led to oxidative stress via the Fenton reaction. On the other hand, the nanomaterials induced ICD-based IMT, which worked jointly with CDT to exhibit excellent effects against lung metastasis of melanoma through a mouse model. This work demonstrated how a nanoplatform, simple and stable but showing excellent efficacy against tumors, could be built using simple building blocks via a self-assembling approach. Importantly, the system took advantage of relatively high levels of GSH and H2O2 in tumors to initiate the therapeutic effects, which rendered the nanoplatform with a capability to differentiate normal cells from tumor cells. In principle, the system has great potential for future clinical applications, not only in the treatment of lung metastasis of melanoma but also in suppressing other types of tumors.


Assuntos
Antineoplásicos/química , Monóxido de Carbono/química , Compostos de Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/metabolismo , Nanopartículas Metálicas/química , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Monóxido de Carbono/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenvolvimento de Medicamentos , Feminino , Glutationa/química , Humanos , Peróxido de Hidrogênio/química , Imunoterapia/métodos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias Experimentais , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
10.
J Clin Lab Anal ; 35(9): e23937, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34396586

RESUMO

OBJECTIVE: To deal with COVID-19, various countries have made many efforts, including the research and development of vaccines. The purpose of this manuscript was to summarize the development, application, and problems of COVID-19 vaccines. METHODS: This article reviewed the existing literature to see the development of the COVID-19 vaccine. RESULTS: We found that different types of vaccines had their own advantages and disadvantages. At the same time, the side effects of the vaccine, the dose of vaccination, the evaluation of the efficacy, and the application of the vaccine were all things worth studying. CONCLUSION: The successful development of the COVID-19 vaccine concerns almost all countries and people in the world. We must do an excellent job of researching the immunogenicity and immune reactivity of the vaccines. We hope this review can help colleagues at home and abroad.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/classificação , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos/métodos , Humanos
11.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443496

RESUMO

Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein-inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Sítios de Ligação , Desenvolvimento de Medicamentos , Humanos
13.
Life Sci Alliance ; 4(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353886

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for more than 3 million deaths in 219 countries across the world and with more than 140 million cases. The absence of FDA-approved drugs against SARS-CoV-2 has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and SARS-CoV-2 to provide insight into the virus' pathogenic mechanism and support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, first, in its healthy state. We then demonstrate how the entry of SARS-CoV-2 into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. A new computational method that predicts 20 unique reactions as drug targets from our models and provides a platform for future studies on viral entry inhibition, immune regulation, and drug optimisation strategies. The model is available in BioModels (https://www.ebi.ac.uk/biomodels/MODEL2007210001) and the software tool, findCPcli, that implements the computational method is available at https://github.com/findCP/findCPcli.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/metabolismo , Desenvolvimento de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , COVID-19/epidemiologia , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Modelos Biológicos , Pandemias
14.
Health Aff (Millwood) ; 40(8): 1243-1251, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34339239

RESUMO

The COVID-19 global pandemic has devastated lives and economies. It has served as a reminder of how critical it is to invest in preventing and treating infectious diseases. Until the COVID-19 pandemic, the largest US government-sponsored reward for infectious disease drug and vaccine development was the Tropical Disease Priority Review Voucher program. Under this program, the Food and Drug Administration awards a priority review voucher to the sponsor of a new drug or vaccine for tropical infectious diseases. The voucher then can be exchanged for the faster review of one drug. We provide case studies for tropical disease voucher recipients between 2007 and 2018, examine the effects of the voucher program on product innovation and access, and recommend that policy makers protect the voucher program while creating complementary incentives.


Assuntos
COVID-19 , Pandemias , Desenvolvimento de Medicamentos , Humanos , SARS-CoV-2 , Estados Unidos , United States Food and Drug Administration
15.
Int J Mol Sci ; 22(15)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34361055

RESUMO

Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , Desenvolvimento de Medicamentos , Glioblastoma/tratamento farmacológico , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos
17.
Pharmazie ; 76(8): 342-350, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412732

RESUMO

Angiotensin-2 converting enzyme (ACE2), a key element of the renin-angiotensin-system (RAS), is not only the direct target of infection by the human SARS-Cov-2 virus but is at the same the root for the complex pathogenetic events of COVID-19. From a pharmaceutical perspective, several established classes of medicines are involved in different phases of the disease. From their known mechanisms of action, a comprehensive understanding of COVID-19 will be hopefully soon delineated. A set of proven medicines is available to cope at least with some of the pathologies involved. To arrive back to normal life, vaccinations and broad consideration of hygienic measures are to be complemented by effective medicines to treat airborne viral infections. Therapeutic schemes based on a comprehensive understanding of the disease will include drug combinations made up from both established drugs as well as novel drugs presently under development.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , Sistema Renina-Angiotensina/fisiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Desenvolvimento de Medicamentos , Humanos , SARS-CoV-2/efeitos dos fármacos
18.
Bull World Health Organ ; 99(7): 482-483, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34248219

RESUMO

The unprecedented speed with which COVID-19 vaccines have been developed and approved reflects increasingly nimble trial procedures, but opportunities exist for greater collaboration. Gary Humphreys and Lynn Eaton report.


Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , COVID-19/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Desenvolvimento de Medicamentos , Humanos , Medição de Risco , Segurança
19.
Comput Biol Chem ; 93: 107536, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34271420

RESUMO

BACKGROUND: Discover possible Drug Target Interactions (DTIs) is a decisive step in the detection of the effects of drugs as well as drug repositioning. There is a strong incentive to develop effective computational methods that can effectively predict potential DTIs, as traditional DTI laboratory experiments are expensive, time-consuming, and labor-intensive. Some technologies have been developed for this purpose, however large numbers of interactions have not yet been detected, the accuracy of their prediction still low, and protein sequences and structured data are rarely used together in the prediction process. METHODS: This paper presents DTIs prediction model that takes advantage of the special capacity of the structured form of proteins and drugs. Our model obtains features from protein amino-acid sequences using physical and chemical properties, and from drugs smiles (Simplified Molecular Input Line Entry System) strings using encoding techniques. Comparing the proposed model with different existing methods under K-fold cross validation, empirical results show that our model based on ensemble learning algorithms for DTI prediction provide more accurate results from both structures and features data. RESULTS: The proposed model is applied on two datasets:Benchmark (feature only) datasets and DrugBank (Structure data) datasets. Experimental results obtained by Light-Boost and ExtraTree using structures and feature data results in 98 % accuracy and 0.97 f-score comparing to 94 % and 0.92 achieved by the existing methods. Moreover, our model can successfully predict more yet undiscovered interactions, and hence can be used as a practical tool to drug repositioning. A case study of applying our prediction model on the proteins that are known to be affected by Corona viruses in order to predict the possible interactions among these proteins and existing drugs is performed. Also, our model is applied on Covid-19 related drugs announced on DrugBank. The results show that some drugs like DB00691 and DB05203 are predicted with 100 % accuracy to interact with ACE2 protein. This protein is a self-membrane protein that enables Covid-19 infection. Hence, our model can be used as an effective tool in drug reposition to predict possible drug treatments for Covid-19.


Assuntos
Antivirais/farmacologia , COVID-19/metabolismo , Desenvolvimento de Medicamentos , Modelos Teóricos , Proteínas/metabolismo , SARS-CoV-2 , Sequência de Aminoácidos , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Aprendizado de Máquina , Proteínas/química
20.
Ther Innov Regul Sci ; 55(5): 1103-1105, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34263440

RESUMO

Government development of new medicines has recently received attention as a means of lowering drug prices. These proposals are generally based on the assumption that the private market charges prices that are higher than justified by the costs of development. Although some costs could be avoided through government drug development, most costs would remain unchanged and some could potentially increase. Inefficiencies that are more difficult to quantify are likely to worsen with greater government involvement in research allocation decisions, including lobbying by industry or patient groups. Government manufacturing is an alluring proposition, but is unlikely in the long term to improve new drug development or lower costs.


Assuntos
Custos de Medicamentos , Indústria Farmacêutica , Custos e Análise de Custo , Desenvolvimento de Medicamentos , Governo , Humanos
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