老药新用抗击新冠肺炎*

新冠肺炎疫情爆发以来,临床上通过老药新用的策略发展小分子药物,以用于治疗新冠肺炎。在短时间内迅速从抗病毒、抗炎药物中发现能够用于新冠治疗的药物,如洛匹那韦/利托那韦、磷酸氯喹等。结合几款典型的药物,浅析它们在抗击新冠肺炎中的应用。     

化学教学新课堂：科学抗疫中的化学知识

As the break out of COVID-19 epidemic, the prevention and control work was consequently carried out. Chemistry plays an important role in the white war. The structure of mask contains the knowledge of interfacial chemistry. The material of mask encompasses the knowledge of polymer chemistry. Nucleic acid test and COVID-19 vaccine research need the knowledge of biological chemistry. The sanitizers involve the knowledge of inorganic and organic chemistry. The knowledge of physical chemistry takes effect in daily hand washing with soap. Each drug against COVID-19 virus was a complex organic compound. All the above things can be taken as appropriate examples in chemistry teaching to display the charm of chemistry. Meanwhile, these examples help students to realize that chemistry works as a vital part in our lives and therefore active their motivation to study chemistry well.     

Comprehensive analyses of bioinformatics applications in the fight against COVID-19 pandemic

Novel coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which can be transmitted from person to person. As of September 21, 2021, over 228 million cases were diagnosed as COVID-19 infection in more than 200 countries and regions worldwide. The death toll is more than 4.69 million and the mortality rate has reached about 2.05% as it has gradually become a global plague, and the numbers are growing. Therefore, it is important to gain a deeper understanding of the genome and protein characteristics, clinical diagnostics, pathogenic mechanisms, and the development of antiviral drugs and vaccines against the novel coronavirus to deal with the COVID-19 pandemic. The traditional biology technologies are limited for COVID-19-related studies to understand the pandemic happening. Bioinformatics is the application of computational methods and analytical tools in the field of biological research which has obvious advantages in predicting the structure, product, function, and evolution of unknown genes and proteins, and in screening drugs and vaccines from a large amount of sequence information. Here, we comprehensively summarized several of the most important methods and applications relating to COVID-19 based on currently available reports of bioinformatics technologies, focusing on future research for overcoming the virus pandemic. Based on the next-generation sequencing (NGS) and third-generation sequencing (TGS) technology, not only virus can be detected, but also high quality SARS-CoV-2 genome could be obtained quickly. The emergence of data of genome sequences, variants, haplotypes of SARS-CoV-2 help us to understand genome and protein structure, variant calling, mutation, and other biological characteristics. After sequencing alignment and phylogenetic analysis, the bat may be the natural host of the novel coronavirus. Single-cell RNA sequencing provide abundant resource for discovering the mechanism of immune response induced by COVID-19. As an entry receptor, angiotensin-converting enzyme 2 (ACE2) can be used as a potential drug target to treat COVID-19. Molecular dynamics simulation, molecular docking and artificial intelligence (AI) technology of bioinformatics methods based on drug databases for SARS-CoV-2 can accelerate the development of drugs. Meanwhile, computational approaches are helpful to identify suitable vaccines to prevent COVID-19 infection through reverse vaccinology, Immunoinformatics and structural vaccinology.     

Nano-Biomimetic Drug Delivery Vehicles: Potential Approaches for COVID-19 Treatment

The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a “Trojan horse” for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed.     

Drug Repurposing for COVID-19: A Review and a Novel Strategy to Identify New Targets and Potential Drug Candidates

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) was first identified in the province of Wuhan, China. Since then, there have been over 400 million confirmed cases and 5.8 million deaths by COVID-19 reported worldwide. The urgent need for therapies against SARS-CoV-2 led researchers to use drug repurposing approaches. This strategy allows the reduction in risks, time, and costs associated with drug development. In many cases, a repurposed drug can enter directly to preclinical testing and clinical trials, thus accelerating the whole drug discovery process. In this work, we will give a general overview of the main developments in COVID-19 treatment, focusing on the contribution of the drug repurposing paradigm to find effective drugs against this disease. Finally, we will present our findings using a new drug repurposing strategy that identified 11 compounds that may be potentially effective against COVID-19. To our knowledge, seven of these drugs have never been tested against SARS-CoV-2 and are potential candidates for in vitro and in vivo studies to evaluate their effectiveness in COVID-19 treatment.     

Molecular docking identification for the efficacy of natural limonoids against COVID-19 virus main protease

COVID-19 pandemic is the biggest public health problem of the century so far.The main protease (Mpro) is one of the main enzymes studied as a pharmacological target. In this context, the present work aimed to perform a virtual screening of possible inhibitors against the enzyme Mpro, having limonoids as the main object of research as supposed inhibitors. Molecular docking simulations indicated that limonoids have an affinity to complex with M-pro.However, Limonine and Nimoliciol showed nonspecific and low affinity interactions. In conclusion, Limonoids are substances of natural origin that can be used in the study of new pharmacological tools designed to combat and understand COVID-19.     

Structure-based virtual screening and molecular dynamics of phytochemicals derived from Saudi medicinal plants to identify potential COVID-19 therapeutics

Coronavirus disease 2019 (COVID-19) has affected almost every country in the world by causing a global pandemic with a high mortality rate. Lack of an effective vaccine and/or antiviral drugs against SARS-CoV-2, the causative agent, has severely hampered the response to this novel coronavirus. Natural products have long been used in traditional medicines to treat various diseases, and purified phytochemicals from medicinal plants provide a valuable scaffold for the discovery of new drug leads. In the present study, we performed a computational screening of an in-house database composed of ~1000 phytochemicals derived from traditional Saudi medicinal plants with recognised antiviral activity. Structure-based virtual screening was carried out against three druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like cysteine protease (3CL^pro) and papain like protease (PL^pro) to identify putative inhibitors that could facilitate the development of potential anti-COVID-19 drug candidates. Computational analyses identified three compounds inhibiting each target, with binding affinity scores ranging from −9.9 to −6.5 kcal/mol. Among these, luteolin 7-rutinoside, chrysophanol 8-(6-galloylglucoside) and kaempferol 7-(6″-galloylglucoside) bound efficiently to RdRp, while chrysophanol 8-(6-galloylglucoside), 3,4,5-tri-O-galloylquinic acid and mulberrofuran G interacted strongly with 3CL^pro, and withanolide A, isocodonocarpine and calonysterone bound tightly to PL^pro. These potential drug candidates will be subjected to further in vitro and in vivo studies and may assist the development of effective anti-COVID-19 drugs.     

Sustainable chemical preventive models in COVID-19: Understanding,innovation, adaptations,and impact

COVID-19 is considered as a major public health problem caused by the SARS CoV-2. This Viral infection is known to induce worldwide pandemic in short period of time. Emerging evidence suggested that the transmission control and drug therapy may influence the preventive measures extensively as the host surrounding environment and pathogenic mechanism may contribute to the pandemic condition earlier in COVID-19 disease. Although, several animals identified as reservoir to date, however human-to-human transmission is well documented. Human beings are sustaining the virus in the communities and act as an amplifier of the virus. Human activities i.e., living with the patient, touching patient waste etc. in the surrounding of active patients or asymptomatic persons cause significant risk factors for transmission. On the other hand, drug target and mechanism to destroy the virus or virus inhibition depends on diversified approaches of drugs and different target for virus life cycle. This article describes the sustainable chemical preventive models understanding, requirements, technology adaptation and the implementation strategies in these pandemic-like situations. As the outbreak progresses, healthcare models focused on transmission control through disinfections and sanitization based on risk calculations. Identification of the most suitable target of drugs and regional control model of transmission are of high priority. In the early stages of an outbreak, availability of epidemiological information is important to encourage preventive measures efforts by public health authorities and provide robust evidence to guide interventions. Here, we have discussed the level of adaptations in technology that research professionals display toward their public health preventive models. We should compile a representative data set of adaptations that humans can consider for transmission control and adopt for viruses and their hosts. Overall, there are many aspects of the chemical science and technology in virus preventive measures. Herein, the most recent advances in this context are discussed, and the possible reasons behind the sustainable preventive model are presented. This kind of sustainable preventive model having adaptation and implementation with green chemistry system will reduce the shedding of the virus into the community by eco-friendly methods, and thus the risk of transmission and infection progression can be mitigated.     

In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19

COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.     

The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.     

Improved HPLC method for the determination of ribavirin concentration in red blood cells and its application in patients with COVID-19

Ribavirin is a synthetic, broad-spectrum antiviral drug. Ribavirin is recommended as an antiviral drug in the Interim Guidance for Diagnosis and Treatment (the seventh edition) of COVID-19. The ribavirin levels in red blood cells may be closely related to both its efficacy and adverse drug reactions. In this study, a simple and fast HPLC–UV method was established to determine the concentrations of total ribavirin in the red blood cells of 13 patients with COVID-19. Phosphorylated ribavirin was dephosphorylated by phosphatase incubation to obtain the total amount of ribavirin in red blood cells. The chromatographic column was an Atlantis C₁₈. The recoveries were 85.45–89.05% at three levels. A good linear response was from 1 to 200 μg/ml, with a correlation coefficient of r² = 0.9991. The concentration of total ribavirin in the red blood cells of the patients ranged from 30.83 to 133.34 μg/ml. The same samples without phosphatase incubation ranged from 4.07 to 20.84 μg/ml. About 85% of ribavirin was phosphorylated in red blood cells. In addition, we observed changes in these patients' hematological parameters and found that the erythrocyte, hemoglobin and hematocrit declined to the lowest levels on the fifth day after discontinuation of ribavirin (p < 0.05).     

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (M^pro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski’s filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as M^pro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.     

The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin–angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.     

Analytical Performance and Greenness Evaluation of Five Multi-Level Design Models Utilized for Impurity Profiling of Favipiravir,a Promising COVID-19 Antiviral Drug

In 2018, the discovery of carcinogenic nitrosamine process related impurities (PRIs) in a group of widely used drugs led to the recall and complete withdrawal of several medications that were consumed for a long time, unaware of the presence of these genotoxic PRIs. Since then, PRIs that arise during the manufacturing process of the active pharmaceutical ingredients (APIs), together with their degradation impurities, have gained the attention of analytical chemistry researchers. In 2020, favipiravir (FVR) was found to have an effective antiviral activity against the SARS-COVID-19 virus. Therefore, it was included in the COVID-19 treatment protocols and was consequently globally manufactured at large-scales during the pandemic. There is information indigence about FVR impurity profiling, and until now, no method has been reported for the simultaneous determination of FVR together with its PRIs. In this study, five advanced multi-level design models were developed and validated for the simultaneous determination of FVR and two PRIs, namely; (6-chloro-3-hydroxypyrazine-2-carboxamide) and (3,6-dichloro-pyrazine-2-carbonitrile). The five developed models were classical least square (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm-partial least squares (GA-PLS), and artificial neural networks (ANN). Five concentration levels of each compound, chosen according to the linearity range of the target analytes, were used to construct a five-level, three-factor chemometric design, giving rise to twenty-five mixtures. The models resolved the strong spectral overlap in the UV-spectra of the FVR and its PRIs. The PCR and PLS models exhibited the best performances, while PLS proved the highest sensitivity relative to the other models.     

The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.     

Discovery,Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase 3 clinical trial against COVID-19. The objective of this review article is to enlighten the researchers working on COVID-19 about the discovery, recent developments, and patents related to molnupiravir. Molnupiravir was originally developed for the treatment of influenza at Emory University, USA. However, this drug has also demonstrated activity against a variety of viruses, including SARS-CoV-2. Now it is being jointly developed by Emory University, Ridgeback Biotherapeutics, and Merck to treat COVID-19. The published clinical data indicate a good safety profile, tolerability, and oral bioavailability of molnupiravir in humans. The patient-compliant oral dosage form of molnupiravir may hit the market in the first or second quarter of 2022. The patent data of molnupiravir revealed its granted compound patent and process-related patent applications. We also anticipate patent filing related to oral dosage forms, inhalers, and a combination of molnupiravir with marketed drugs like remdesivir, favipiravir, and baricitinib. The current pandemic demands a patient compliant, safe, tolerable, and orally effective COVID-19 treatment. The authors believe that molnupiravir meets these requirements and is a breakthrough COVID-19 treatment.     

疫情影响下的全球治理：碎片化与中等强国的角色

世界正面临着第二次世界大战以来最严重的全球危机。不仅各国政府正在尽其所能改善国内公共卫生管理,而且国际社会也迫切需要改善全球治理。然而,面对这场全球性危机,世界没有应有的团结。相反,美国推进对抗性竞争战略以维护世界霸权,其政客试图将预防和控制政治化,破坏全球协调机制。这使得全球治理的缺陷进一步暴露,碎片化趋势进一步呈现,大国竞争及权势转移的趋势更为明显。可预见的未来,全球治理进程更有可能采用区域形式。适应全球治理的迫切需求,中等强国在全球治理中的多重作用空间显著扩大,多数选择平衡外交政策,力主践行多边主义,扮演“催化剂”“搭桥者”角色,赢得全球影响力;不过“追随者”角色也让部分中等强国暴露出能力上的弱点与外交独立性的不足。     

Nigella sativa L. and COVID-19: A Glance at The Anti-COVID-19 Chemical Constituents,Clinical Trials,Inventions, and Patent Literature

COVID-19 has had an impact on human quality of life and economics. Scientists have been identifying remedies for its prevention and treatment from all possible sources, including plants. Nigella sativa L. (NS) is an important medicinal plant of Islamic value. This review highlights the anti-COVID-19 potential, clinical trials, inventions, and patent literature related to NS and its major chemical constituents, like thymoquinone. The literature was collected from different databases, including Pubmed, Espacenet, and Patentscope. The literature supports the efficacy of NS, NS oil (NSO), and its chemical constituents against COVID-19. The clinical data imply that NS and NSO can prevent and treat COVID-19 patients with a faster recovery rate. Several inventions comprising NS and NSO have been claimed in patent applications to prevent/treat COVID-19. The patent literature cites NS as an immunomodulator, antioxidant, anti-inflammatory, a source of anti-SARS-CoV-2 compounds, and a plant having protective effects on the lungs. The available facts indicate that NS, NSO, and its various compositions have all the attributes to be used as a promising remedy to prevent, manage, and treat COVID-19 among high-risk people as well as for the therapy of COVID-19 patients of all age groups as a monotherapy or a combination therapy. Many compositions of NS in combination with countless medicinal herbs and medicines are still unexplored. Accordingly, the authors foresee a bright scope in developing NS-based anti-COVID-19 composition for clinical use in the future.