Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the Mpro and PLpro enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.

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Emergence of SARS-CoV-2 through recombination and strong purifying selection

Science Advances ◽

10.1126/sciadv.abb9153 ◽

2020 ◽

Vol 6 (27) ◽

pp. eabb9153 ◽

Cited By ~ 49

Author(s):

Xiaojun Li ◽

Elena E. Giorgi ◽

Manukumar Honnayakanahalli Marichannegowda ◽

Brian Foley ◽

Chuan Xiao ◽

...

Keyword(s):

Host Species ◽

Purifying Selection ◽

New Drugs ◽

Evolutionary Constraints ◽

Binding Motif ◽

The Novel ◽

Global Pandemic ◽

Show Evidence ◽

Human Coronaviruses ◽

Novel Coronavirus

COVID-19 has become a global pandemic caused by the novel coronavirus SARS-CoV-2. Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis, discovering new drugs, and developing a vaccine. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike and other genes among bat, pangolin, and human coronaviruses, suggesting similar evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2’s entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2’s ability to infect humans. Similar purifying selection in different host species, together with frequent recombination among coronaviruses, suggests a common evolutionary mechanism that could lead to new emerging human coronaviruses.

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Pharmacological strategies for COVID-19 - A review of the most promising repurposed antiviral drugs.

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666201218151841 ◽

2020 ◽

Vol 20 ◽

Author(s):

Deepti Chopra ◽

Jaspreet K Boparai ◽

Bharti Bhandari ◽

Anurag Srivastava ◽

Rakesh Gupta

Keyword(s):

Clinical Experience ◽

Clinical Studies ◽

Antiviral Drugs ◽

New Drugs ◽

Present Review ◽

Safety And Efficacy ◽

Global Challenge ◽

Antiviral Therapies ◽

Novel Coronavirus

: A novel coronavirus, SARS-CoV-2 (2019-nCoV) emerged in December 2019 as an immediate global challenge. Comprehensive efforts at present time are focused simultaneously on containing spread of this virus and extenuating the ill effects. There is an immediate need for drugs that can help before a vaccine can be developed. Researchers are endeavoring to find antiviral therapies specific to the virus. As the condition is an emerging, rapidly evolving situation and development of new drugs is a long process, and is unfeasible to face the immediate global challenge. Strategy to reposition the previously used drugs can prove to be effective to combat this difficult to treat situation. Several drugs such as Hydroxychloroquine, Umifenovir, Remdesivir, Lopinavir/Ritonavir, interferon, Darunavir, Favipiravir, Nitazoxanide etc. are currently undergoing clinical studies to test the safety and efficacy of the drug against this pandemic. The present review gives a snapshot look of the current clinical experience with repurposed antiviral drugs.

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Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

Current Medicinal Chemistry ◽

10.2174/0929867327666200730213215 ◽

2020 ◽

Vol 27 ◽

Author(s):

Reyaz Hassan Mir ◽

Abdul Jalil Shah ◽

Roohi Mohi-ud-din ◽

Faheem Hyder Potoo ◽

Mohd. Akbar Dar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Protective Action ◽

New Drugs ◽

Huperzine A ◽

Brain Disorder ◽

Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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Natural Products for the Treatment of Neurodegenerative Diseases

Current Medicinal Chemistry ◽

10.2174/0929867326666190527120614 ◽

2020 ◽

Vol 27 (34) ◽

pp. 5790-5828 ◽

Cited By ~ 1

Author(s):

Ze Wang ◽

Chunyang He ◽

Jing-Shan Shi

Keyword(s):

Nervous System ◽

Natural Products ◽

Neurodegenerative Diseases ◽

Neuroprotective Effect ◽

Rapid Development ◽

New Drugs ◽

Progressive Degeneration ◽

Cord Injury ◽

The Central Nervous System ◽

And Function

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's Disease (AD), Parkinson's Disease (PD) and Spinal Cord Injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the Traditional Chinese Medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

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MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.557 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii406-iii406

Author(s):

Kübra Taban ◽

David Pauck ◽

Mara Maue ◽

Viktoria Marquardt ◽

Hua Yu ◽

...

Keyword(s):

New Drugs ◽

Current Therapy ◽

Cancer Drug ◽

Mrna Levels ◽

Cell Models ◽

Therapeutic Approaches ◽

Group 3 ◽

Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

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Genetic Variation and Evolution of the 2019 Novel Coronavirus

Public Health Genomics ◽

10.1159/000513530 ◽

2021 ◽

pp. 1-13

Author(s):

Salvatore Dimonte ◽

Muhammed Babakir-Mina ◽

Taib Hama-Soor ◽

Salar Ali

Keyword(s):

Amino Acid ◽

Receptor Binding ◽

Rapid Evolution ◽

Single Amino Acid ◽

Angiotensin Converting Enzyme 2 ◽

New Type ◽

Amino Acid Mutations ◽

Host Infection ◽

Human Coronaviruses ◽

Novel Coronavirus

Introduction: SARS-CoV-2 is a new type of coronavirus causing a pandemic severe acute respiratory syndrome (SARS-2). Coronaviruses are very diverting genetically and mutate so often periodically. The natural selection of viral mutations may cause host infection selectivity and infectivity. Methods: This study was aimed to indicate the diversity between human and animal coronaviruses through finding the rate of mutation in each of the spike, nucleocapsid, envelope, and membrane proteins. Results: The mutation rate is abundant in all 4 structural proteins. The most number of statistically significant amino acid mutations were found in spike receptor-binding domain (RBD) which may be because it is responsible for a corresponding receptor binding in a broad range of hosts and host selectivity to infect. Among 17 previously known amino acids which are important for binding of spike to angiotensin-converting enzyme 2 (ACE2) receptor, all of them are conservative among human coronaviruses, but only 3 of them significantly are mutated in animal coronaviruses. A single amino acid aspartate-454, that causes dissociation of the RBD of the spike and ACE2, and F486 which gives the strength of binding with ACE2 remain intact in all coronaviruses. Discussion/Conclusion: Observations of this study provided evidence of the genetic diversity and rapid evolution of SARS-CoV-2 as well as other human and animal coronaviruses.

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Natural Products Targeting the Mitochondria in Cancers

Molecules ◽

10.3390/molecules26010092 ◽

2020 ◽

Vol 26 (1) ◽

pp. 92

Author(s):

Yue Yang ◽

Ping-Ya He ◽

Yi Zhang ◽

Ning Li

Keyword(s):

Natural Products ◽

Anticancer Drugs ◽

Web Of Science ◽

Keyword Search ◽

Biological Activities ◽

Natural Compounds ◽

New Drugs ◽

Antitumor Effects ◽

Regulate Cell Growth ◽

Anticancer Drug Discovery

There are abundant sources of anticancer drugs in nature that have a broad prospect in anticancer drug discovery. Natural compounds, with biological activities extracted from plants and marine and microbial metabolites, have significant antitumor effects, but their mechanisms are various. In addition to providing energy to cells, mitochondria are involved in processes, such as cell differentiation, cell signaling, and cell apoptosis, and they have the ability to regulate cell growth and cell cycle. Summing up recent data on how natural products regulate mitochondria is valuable for the development of anticancer drugs. This review focuses on natural products that have shown antitumor effects via regulating mitochondria. The search was done in PubMed, Web of Science, and Google Scholar databases, over a 5-year period, between 2015 and 2020, with a keyword search that focused on natural products, natural compounds, phytomedicine, Chinese medicine, antitumor, and mitochondria. Many natural products have been studied to have antitumor effects on different cells and can be further processed into useful drugs to treat cancer. In the process of searching for valuable new drugs, natural products such as terpenoids, flavonoids, saponins, alkaloids, coumarins, and quinones cover the broad space.

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Natural and Nature-Derived Products Targeting Human Coronaviruses

Molecules ◽

10.3390/molecules26020448 ◽

2021 ◽

Vol 26 (2) ◽

pp. 448

Author(s):

Konstantina Vougogiannopoulou ◽

Angela Corona ◽

Enzo Tramontano ◽

Michael N. Alexis ◽

Alexios-Leandros Skaltsounis

Keyword(s):

Natural Products ◽

Antiviral Agents ◽

Critical Perspective ◽

Human Coronavirus ◽

State Of Emergency ◽

Pharmacological Agents ◽

Pure Compounds ◽

Total Plant ◽

Human Coronaviruses ◽

The 1960S

The ongoing pandemic of severe acute respiratory syndrome (SARS), caused by the SARS-CoV-2 human coronavirus (HCoV), has brought the international scientific community before a state of emergency that needs to be addressed with intensive research for the discovery of pharmacological agents with antiviral activity. Potential antiviral natural products (NPs) have been discovered from plants of the global biodiversity, including extracts, compounds and categories of compounds with activity against several viruses of the respiratory tract such as HCoVs. However, the scarcity of natural products (NPs) and small-molecules (SMs) used as antiviral agents, especially for HCoVs, is notable. This is a review of 203 publications, which were selected using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, evaluates the available literature since the discovery of the first human coronavirus in the 1960s; it summarizes important aspects of structure, function, and therapeutic targeting of HCoVs as well as NPs (19 total plant extracts and 204 isolated or semi-synthesized pure compounds) with anti-HCoV activity targeting viral and non-viral proteins, while focusing on the advances on the discovery of NPs with anti-SARS-CoV-2 activity, and providing a critical perspective.

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Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study

Molecules ◽

10.3390/molecules26061616 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1616

Author(s):

Nicoletta di Leo ◽

Stefania Moscato ◽

Marco Borso' ◽

Simona Sestito ◽

Beatrice Polini ◽

...

Keyword(s):

High Performance ◽

In Vitro Model ◽

New Drugs ◽

Therapeutic Approaches ◽

Neuroprotective Effects ◽

Pharmacological Response ◽

Preliminary Study ◽

Vitro Model ◽

The Brain

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.

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Eremophilane-type sesquiterpenes from fungi and their medicinal potential

Biological Chemistry ◽

10.1515/hsz-2017-0171 ◽

2017 ◽

Vol 399 (1) ◽

pp. 13-28 ◽

Cited By ~ 10

Author(s):

Kamila Tomoko Yuyama ◽

Diana Fortkamp ◽

Wolf-Rainer Abraham

Keyword(s):

Fatty Acids ◽

Natural Products ◽

Carbon Skeleton ◽

New Drugs ◽

Special Focus ◽

Bioactive Natural Products ◽

Pharmacokinetic Assessment ◽

Immunomodulatory Properties ◽

Chemical Tools ◽

Subsequent Improvement

AbstractEremophilanes are sesquiterpenes with a rearranged carbon skeleton formed both by plants and fungi, however, almost no plant eremophilanes are found in fungi. These eremophilanes possess mainly phytotoxic, antimicrobial, anticancer and immunomodulatory properties and in this review fungal eremophilanes with bioactivities of potential medicinal applications are reviewed and discussed. A special focus is set on natural products bearing highly functionalized fatty acids at C-1 or C-3 position of the eremophilane backbone. Many of these fatty acids seem to contribute to the bioactivity of the metabolites enhancing the activity of the sesquiterpene moieties. Several approaches for optimization of these natural products for clinical needs and testing of the resulting derivatives are presented and discussed. The combination of identification of bioactive natural products with their subsequent improvement using a variety of genetical or chemical tools and the pharmacokinetic assessment of the products is presented here as a promising approach to new drugs.

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