Progress on COVID-19 Chemotherapeutics Discovery and Novel Technology

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel highly contagious and pathogenic coronavirus that emerged in late 2019. SARS-CoV-2 spreads primarily through virus-containing droplets and small particles of air pollution, which greatly increases the risk of inhaling these virus particles when people are in close proximity. COVID-19 is spreading across the world, and the COVID-19 pandemic poses a threat to human health and public safety. To date, there are no specific vaccines or effective drugs against SARS-CoV-2. In this review, we focus on the enzyme targets of the virus and host that may be critical for the discovery of chemical compounds and natural products as antiviral drugs, and describe the development of potential antiviral drugs in the preclinical and clinical stages. At the same time, we summarize novel emerging technologies applied to the research on new drug development and the pathological mechanisms of COVID-19.     

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.     

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。     

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.     

Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.     

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.     

Potential of graphene-based materials to combat COVID-19: properties,perspectives, and prospects

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new virus in the coronavirus family that causes coronavirus disease (COVID-19), emerges as a big threat to the human race. To date, there is no medicine and vaccine available for COVID-19 treatment. While the development of medicines and vaccines are essentially and urgently required, what is also extremely important is the repurposing of smart materials to design effective systems for combating COVID-19. Graphene and graphene-related materials (GRMs) exhibit extraordinary physicochemical, electrical, optical, antiviral, antimicrobial, and other fascinating properties that warrant them as potential candidates for designing and development of high-performance components and devices required for COVID-19 pandemic and other futuristic calamities. In this article, we discuss the potential of graphene and GRMs for healthcare applications and how they may contribute to fighting against COVID-19.     

新型冠状病毒检测以及相关药物研发中的基础药学知识

Abundant basic pharmaceutical knowledge is involved in the detection of SARS-CoV-2 and the discovery and development of antiviral drugs. This paper gives detailed summary and provides rich materials for case teaching.     

A Comprehensive Review of Andrographis paniculata (Burm. f.) Nees and Its Constituents as Potential Lead Compounds for COVID-19 Drug Discovery

The COVID-19 pandemic has intensively disrupted global health, economics, and well-being. Andrographis paniculata (Burm. f.) Nees has been used as a complementary treatment for COVID-19 in several Asian countries. This review aimed to summarize the information available regarding A. paniculata and its constituents, to provide critical points relating to its pharmacological properties, safety, and efficacy, revealing its potential to serve as a source of lead compounds for COVID-19 drug discovery. A. paniculata and its active compounds possess favorable antiviral, anti-inflammatory, immunomodulatory, and antipyretic activities that could be beneficial for COVID-19 treatment. Interestingly, recent in silico and in vitro studies have revealed that the active ingredients in A. paniculata showed promising activities against 3CLpro and its virus-specific target protein, human hACE2 protein; they also inhibit infectious virion production. Moreover, existing publications regarding randomized controlled trials demonstrated that the use of A. paniculata alone or in combination was superior to the placebo in reducing the severity of upper respiratory tract infection (URTI) manifestations, especially as part of early treatment, without serious side effects. Taken together, its chemical and biological properties, especially its antiviral activities against SARS-CoV-2, clinical trials on URTI, and the safety of A. paniculata, as discussed in this review, support the argument that A. paniculata is a promising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.     

Synthesis and Applications of Peptides and Peptidomimetics in Drug Discovery

Peptides are described as naturally occurring short chains of amino acids and offer great potential as therapeutic agents because of their target selectivity, safe, and well tolerable. Hence, there is an increased interest in peptides in pharmaceutical research and development and approximately more than 170 peptide therapeutics are currently being evaluated in clinical trials and many are being used as therapeutic drugs for various diseases including COVID-19. The present Review article focuses on recent progress in peptide drug discovery and advancements in synthetic methodologies to enhance their stability and physiological activity of peptides and as well peptidomimetics.     

DrugDevCovid19: An Atlas of Anti-COVID-19 Compounds Derived by Computer-Aided Drug Design

Since the outbreak of SARS-CoV-2, numerous compounds against COVID-19 have been derived by computer-aided drug design (CADD) studies. They are valuable resources for the development of COVID-19 therapeutics. In this work, we reviewed these studies and analyzed 779 compounds against 16 target proteins from 181 CADD publications. We performed unified docking simulations and neck-to-neck comparison with the solved co-crystal structures. We computed their chemical features and classified these compounds, aiming to provide insights for subsequent drug design. Through detailed analyses, we recommended a batch of compounds that are worth further study. Moreover, we organized all the abundant data and constructed a freely available database, DrugDevCovid19, to facilitate the development of COVID-19 therapeutics.     

Synthesis and molecular docking study of novel COVID-19 inhibitors

In 2020, the world tried to combat the corona virus (COVID-19) pandemic. A proven treatment method specific to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is still not found. In this study, seven new antiviral compounds were designed for COVID-19 treatment. The ability of these compounds to inhibit COVID-19’s RNA processing was calculated by the molecular docking study. It has been observed that the compounds can have high binding affinities especially against NSP12 (between -9.06 and -8.00 kcal/mol). The molecular dynamics simulation of NSP12-ZG 7 complex proved the stability of interaction. The synthesis of two most active molecules was performed by one-pot reaction and characterized by FT-IR, ¹H-NMR, ¹³C-NMR, and mass spectroscopy. The compounds presented with their synthesis are inhibitory core structures against SARS-CoV-2 infection.     

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.     

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.     

Molecular and Structural Analysis of Specific Mutations from Saudi Isolates of SARS-CoV-2 RNA-Dependent RNA Polymerase and their Implications on Protein Structure and Drug–Protein Binding

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has stressed the global health system to a significant level, which has not only resulted in high morbidity and mortality but also poses a threat for future pandemics. This situation warrants efforts to develop novel therapeutics to manage SARS-CoV-2 in specific and other emerging viruses in general. This study focuses on SARS-CoV2 RNA-dependent RNA polymerase (RdRp) mutations collected from Saudi Arabia and their impact on protein structure and function. The Saudi SARS-CoV-2 RdRp sequences were compared with the reference Wuhan, China RdRp using a variety of computational and biophysics-based approaches. The results revealed that three mutations—A97V, P323I and Y606C—may affect protein stability, and hence the relationship of protein structure to function. The apo wild RdRp is more dynamically stable with compact secondary structure elements compared to the mutants. Further, the wild type showed stable conformational dynamics and interaction network to remdesivir. The net binding energy of wild-type RdRp with remdesivir is -50.76 kcal/mol, which is more stable than the mutants. The findings of the current study might deliver useful information regarding therapeutic development against the mutant RdRp, which may further furnish our understanding of SARS-CoV-2 biology.     

State-of-the-art colloidal particles and unique interfaces-based SARS-CoV-2 detection methods and COVID-19 diagnosis

In March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-based infections were declared ‘COVID-19 pandemic’ by the World Health Organization. Pandemic raised the necessity to design and develop genuine and sensitive tests for precise specific SARS-CoV-2 infections detection. Nanotechnological methods offer new ways to fight COVID-19. Nanomaterials are ideal for unique sensor platforms because of their chemically versatile properties and they are easy to manufacture. In this context, selected examples for integrating nanomaterials and distinct biosensor platforms are given to detect SARS-CoV-2 biological materials and COVID-19 biomarkers, giving researchers and scientists more goals and a better forecast to design more relevant and novel sensor arrays for COVID-19 diagnosis.     

Efficacy of Phytochemicals Derived from Avicennia officinalis for the Management of COVID-19: A Combined In Silico and Biochemical Study

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.