key: cord-0737208-3pcmz444
authors: Monticolo, Francesco; Palomba, Emanuela; De Santis, Rosa; Assentato, Lorenzo; Triscino, Viviana; Langella, Maria Chiara; Lanzotti, Virginia; Chiusano, Maria Luisa
title: anti-HCoV: A web resource to collect natural compounds against human coronaviruses
date: 2020-09-22
journal: Trends Food Sci Technol
DOI: 10.1016/j.tifs.2020.09.007
sha: 90fc8274e63dcb77e470ccd7104917651648b77c
doc_id: 737208
cord_uid: 3pcmz444

BACKGROUND: . A novel coronavirus, the SARS-CoV2, was revealed to be the cause of COVID19, the pandemic disease that already provoked more than 555.324 deaths in the world (July 10, 2020). No vaccine treatment has been defined against SARS-CoV2 or other human coronaviruses (HCoVs), including those causing epidemic infections, neither appropriate strategies for prevention and care are yet officially suggested. SCOPE AND APPROACH: . We reviewed scientific literature on natural compounds that were defined as potentially effective against human coronaviruses. Our desk research identified non-chemically modified natural compounds that were shown (in vitro) and/or predicted (in silico) to act against one or more phases of human coronaviruses cell cycle. We selected all available information, merged and annotated the data to define a comprehensive list of natural compounds, describing their chemical classification, the source, the action, the specific target in the viral infection. Our aim was to collect possible compounds for prevention and care against human coronaviruses. KEY FINDINGS AND CONCLUSIONS: . The definition of appropriate interventions against viral diseases need a comprehensive view on the infection dynamics and on necessary treatments. Viral targeting compounds to be exploited in food sciences could be of relevant interest to this aim. We collected 174 natural compounds showing effects against human infecting coronaviruses, providing a curated annotation on actions and targets. The data are available in anti-HCoV, a web accessible resource to be exploited for testing and in vivo trials. The website is here launched to favour a community based cooperative effort to call for contribution and expand the collection. To be ready to fight.

1) The new SARS-CoV2 caused more than 555.000 deaths in seven months 12 2) HCoVs similarities suggest possible similar action against them 13

3) No official treatment for prevention and care against HCoVs is yet approved 14 4) In silico and experimental analyses revealed effective compounds against HCoVs 15 5) Comprehensive collections of natural compounds against HCoVs are a resource 16 17 Abstract 18

A novel coronavirus, the SARS-CoV2, was revealed to be the cause of COVID19, the pandemic disease that 20 already provoked more than 555.324 deaths in the world (July 10, 2020). No vaccine treatment has been 21 defined against SARS-CoV2 or other human coronaviruses (HCoVs), including those causing epidemic 22

infections, neither appropriate strategies for prevention and care are yet officially suggested. 23

We reviewed scientific literature on natural compounds that were defined as potentially effective against 25 human coronaviruses. Our desk research identified non-chemically modified natural compounds that were 26

shown (in vitro) and/or predicted (in silico) to act against one or more phases of human coronaviruses cell 27 cycle. 28 We selected all available information, merged and annotated the data to define a comprehensive list of 29 natural compounds, describing their chemical classification, the source, the action, the specific target in the 30 viral infection. Our aim was to collect possible compounds for prevention and care against human 31 coronaviruses. 32 33

Key findings and conclusions 34

The definition of appropriate interventions against viral diseases need a comprehensive view on the 35 infection dynamics and on necessary treatments. Viral targeting compounds to be exploited in food 36 sciences could be of relevant interest to this aim. 37

We collected 174 natural compounds showing effects against human infecting conoraviruses, providing a 38 curated annotation on actions and targets. 39

The data are available in anti-HCoV, a web accessible resource to be exploited for testing and in vivo trials. 40 The website is here launched to favour a community based cooperative effort to call for contribution and 41 expand the collection. To be ready to fight.

(from the tunicate Ecteinascidia turbinata). The former is used to relieve severe and chronic pain, whereas, 97 the latter is used to treat cancer (Lobo-Ruiz & Tulla-Puche, 2018). 98 Marine organisms are also of interests as source of NPs. Seaweeds, as an example, have been considered 99

for their anti-tumor, anti-inflammatory, anti-lipidemic and anti-viral properties. It has been reported that 100 some sulphated polysaccharides extracted from red algae show antiviral activity. In particular, galactan 101 sulphate (from Aghardhiella tenera) and xylomannan sulphate (from Nothogenia fastigiata) exhibit antiviral 102 activity against human immunodeficiency virus, herpes simplex viruses types 1, 2 and respiratory syncytial 103

virus (Pal et al., 2014) . papillomavirus, hepatitis, influenza, chikungunya, herpes simplex 2, and Zika viruses (ZIKV)). 110

In the past two decades, coronaviruses have caused three epidemic diseases: SARS-CoV2 (Zhou et al., 111 2020), the severe acute respiratory syndrome (SARS) (Rota et al., 2003) The N protein functions primarily by binding the viral genome and organizing it as a nucleocapsid. 182

Putatively, it can also contribute to the virion formation. The M protein defines the shape of the envelope, 183

promotes the final viral assembly, and together with the E protein forms the envelope. The E protein is the 184 smallest viral protein inside the infected cells, but only a small portion is incorporated into the virion 185 envelope. The S protein mediates the attachment of the virus to the host cell membrane receptor (Xia et  186 al., 2020). Because of its role in starting the viral infection, the S proteins are particularly of interest since 187 they also determine the efficiency of the infection and its spreading (Zhou et al., 2020) . 188

Spike proteins have two subunits, the amino-terminal receptor binding (S1) and the carboxy-terminal 189 membrane fusion (S2) domains. The S1 domain includes the receptor binding domain (RBD), which is the 190 region binding the host receptor, that determines tissue tropism and host range variability for different 191 CoVs ( Figure 1 ). The cleavage at the junction between the S1 and the S2 domains activates membrane 192 fusion, a process called the S protein priming, and that is crucial to determine the viral entry into the cell 193 (Zhou et al., 2020) . anti-viral role against HCoV-229E (Table S1 ). To this end, they performed anti-HCoV assays infecting viral 221 susceptible MRC-5 fibroblast cells from lung, treating them with the extracted compounds for 2 h at 37°C 222 (Chang et al., 2012) . 223

Interestingly, the bioactivity assays revealed a strong antiviral activity influenced by the chemical structure 224 of the selected compounds. For instance, considering the friedelane derivatives, the antiviral activity of the 225 two epimers, 3β-friedelanol and 3α-friedelanol, was substantially affected by a different orientation of the 226 C-3 proton. Moreover, the comparison of 3β-friedelanol and 3β-acetoxy friedelane suggested the 227 involvement of the acetyl group in the reduction of the activity. performed an inhibition assay to evaluate viral proteases activity after exposure to 10 plant root derived 267 glucosidase inhibitors (Table S1 ). They found that all isolated polyphenols can inhibit both 3CL and PLpro 268 proteases, and that, among them, papyriflavonol A has its highest activity against PLpro (IC 50 = 3.7 μM). 269 (Park et al., 2017) . traditional Chinese herbs. These two molecules had been already reported to have also antimicrobial 276 effects. The two molecules showed detectable antiviral activities on foetal rhesus kidney-4 (fRhK-4) 277

infected with the 10 strains (EC 50 for baicalin at 48 hours was from 12.5 to 25 µg/ml). However, their 278 activities showed a decrease after 48 hours treatments (F. Chen et al., 2004) . 279

Among the compound tested, the authors suggested the baicalin for both prophylaxis or treatment SARS-280

CoV infectious desease. The intravenous administration of a 360 mg dose of that compound in human can 281

achieve an active serum concentration of 74 µg/ml. Despite its mechanism of action against SARS-CoV is 282 not known, regarding HIV-1 infections, baicalin was shown to inhibit the infection process both at cellular 283 entry and through the inhibition of HIV-1 reverse transcriptase. In particular, its binding with the 284 chemokines MIP-1β and SDF-1α prevented the activation of both CCR5 and CXCR4 cellular receptors, which 285 are essential for HIV-1 cellular entry. 286 287

In 2003, Cinatl et al. (Cinatl et al., 2003) tested glycyrrhizin against two clinical isolates of SARS-288 coronaviruses (FFM-1 and FFM-2). The glycyrrhizic acid is a triterpene glycoside extracted from the root of 289 the licorice plant (Glycyrrhiza glabra), with many properties such as anti-inflammatory, anti-viral, 290

hepatoprotective and anticancer activities. The authors also showed that the maximum effect of 291 glycyrrhizin (EC 50 = 300 mg/L) was obtained when administered during and after the viral adsorption in 292

Vero E6 cells, the African green monkey kidney cell line. Despite the glycyrrhizin had never been tested 293 against SARS-COVs infected patients, the administration of the compound effectively decreased the 294 concentrations of P24 antigen and prevented the development of hepatocellular carcinoma in those 295

infected by HIV-1 and chronic hepatitis C virus, respectively (Busia, 2017) . Since side-effects were reported 296

after several months of glycyrrhizin treatment, the authors suggested that the treatments should last for a 297 short period. Despite the mechanism of the antiviral activity against SARS-CoV remains unclear, the authors 298

suggested that it could be related to the upregulation of the inducible nitrous oxide synthase and, as a 299 consequence, to the increased production of nitrous oxide that is proposed to be an inhibitor of SARS-CoV 300

replication. 301

Results on the inhibition of viral adsorption were also found by Keyaerts (TAMRA)) at the same terminus. Therefore, a constant FRET reaction between FAM and TAMRA occurred 322 when the two DNA strands were base-paired; however, this interaction is lost as soon as the duplex is 323 unwound by the viral helicase. Using this experimental approach, they excluded that the 64 natural 324 compounds (that they screened) interfered with the DNA unwinding activity of the viral helicase protein. inhibition are 2.4 ± 0.2, 34.5 ± 2.6, 43.2 ± 14.1, and 88.2 ± 7.7 μg/ml, respectively). Because of its efficiency, 360 the authors focused on Lycoris radiate extracts, demonstrating that the alkaloid lycorine (Table S1) (TF2B)  367 and Theaflavin-3,3'-digallate (TF3) (polyphenols in black tea), selected from the pure Natural Products 368

Library (https://www.nccih.nih.gov/grants/natural-product-libraries), are able to inhibit the 50% of the 369 proteolytic activity of SARS-CoV 3CLpro (expressed in E. coli), at concentrations < 10 µM (IC 50 = 3, 3.7 and 370 9.5 µM respectively). Despite the mechanism of action of these extracts was still unknown, the authors 371 suggested that TF2B and TF3 are inhibitors of SARS-CoV 3CLpro more effective than other compounds (i.e 372 TF1) probably for the presence of a gallate group that could have an important role in directing their 373 inhibitory effect against SARS-CoV 3CLpro. 374 375

Results on the inhibition role on SARS-CoV 3CLpro were also reported for quercetin-3-β-galactoside by 376 Chen COVID19 related genes, identifying 24 disease-related human pathways and 78 potential drugs, that could 412 be repurposed. They manually filtered the list of drugs based on their "mechanisms of action", "adverse 413 effects", and "clinical approvals", yielding to a total of 30 drugs (X. Li et al., 2020) . From their collection, we 414 selected 11 natural compounds, ( of the natural compounds among those predicted with an antiviral activity, therefore identifying potential 430 effective antiviral active herbs (Table 1 .b). The authors also evaluated the absorption, distribution, 431 metabolism and excretion of the compounds, after boiling in water and oral assumption, based on the 432 traditional chinese medical treatments (D.-H. . Since the authors did not list the specific 433 compounds per herb in their work, we re-analyzed the different databases to identify the exact 434 correspondence (Table 1 .b), so that we could report the complete list also in Table S1 . Specifically, starting 435 from the list of the 13 natural compounds identified by the authors we cross-searched for these 436 compounds in the three databases they indicated in their work, i. and, therefore, we could report the compound and the corresponding herbal plants (Table 1 were new in our collection (Table S1) . 455

Safety and Clinical trials 457 458

Although it is not the main aim of this work, it is worthy to underline in this context that also for NPs the 459 development of a new treatment, medicine, or any employment in food industry requires assessments of 460 compounds safety, which is an important issue to be addressed in drug development and the cause of drug 461 candidate attrition in the biopharmaceutical industry. Decision of any eployment can only be made if both 462 benefits and risks are addressed. The aim of safety tests, indeed, is to improve risk-benefit assessment at all 463 stages of drug development (Roberts, 2018) . Internationally accepted guidelines were developed to 464 monitor drugs, foods and also environmental contaminants for adverse reactions and toxicity and to ensure 465 their safety. 466

A drug's disposition depends upon the absorption process from a dosing site, the distribution to target and 467 other systemic and peripheral tissues, and the elimination of unchanged drug by metabolism or excretion. 468

These processes interact to characterize a drug by its pharmacokinetic profile and any alteration will have 469 an impact on the drug safety and efficacy. Therefore, methods were developed by pharmaceutical chemists 470

to predict drug absorption, distribution, metabolism, interaction and also the excretion of unchanged drug 471 and the effect with potential adverse outcomes, thus compromising a drug's safety profile (Roberts, 2018 

Over the past decades, efforts have been done by the pharmaceutical industry to the development, 477 evaluation, and implementation of in vitro alternatives to animal testing in the hazard identification and 478 risk assessment of preclinical drug candidates (Goh et al., 2015) . 479

The safety assessment of drugs requires first testing in toxicology species prior to human studies (Guideline 480 & others, 2009). Toxicological assessment and translational of toxicity data from animal species to human 481 are often challenged since it was suggested that 70% of human-relevant toxicities are identified in 482 toxicology species (Olson et al., 2000) . 483

Although the detection of toxicity is dependent by organ and species, its absence in two different species is 484 strongly predictive of the absence of toxicity in humans. In general, human adverse drug reaction (ADR) is 485 associated mainly to hepatic, cardiovascular and neurological toxicities (Olson et al., 2000) . 486

Drug-drug interaction (DDI) constitutes one of the potential mechanisms leading to often preventable ADR 487 and health damage. In fact, multiple drug therapies are very common for the treatment of various medical 488 illnesses thus being a potential source of DDI and of drug failure (Edwards & Aronson, 2000) . 489

Thus, the understanding of the on-and off-target mechanisms that are responsible of ADR give the 490 opportunity to evaluate target organ toxicity earlier in drug discovery and with a greater specificity. 491

Safety is also inherent the use of NP from raw materials for food formulation regarding their origin and individuals is given the investigational product, generating crucial safety and efficacy data. 498

Among the compounds listed in Table S1 , 19 are already included in the clinical trials database, 499

ClinicalTrials.gov, for their exploitation as antiviral compounds (https://clinicaltrials.gov/) (Table S1) . Among 500 these, only the tannic acid, the curcumin and the aescin have been selected to undergo clinical trials for 501 testing their efficacy in patients affected by human coronavisuses. In particular, they are all being tested for 502 their efficacy against SARS-CoV2. In the randomized controlled trial on tannin specific natural extract 503 (NCT04403646), the molecular complex ARBOX, composed by quebracho, Vit B12 and chestnut tannins 504 extracts, is being tested as a dietary supplement in patient infected by SARS-CoV2 in addition to the 505 conventional standard therapy (including antipyretics or lopinavir/ritonavir, azithromycin and 506 hydroxychloroquine). 507

As for the tannin extracts, another ongoing trial using the compound aescin (NCT04322344) aims to 508 evaluate its efficacy and safety as an adjuvant to conventional antiviral drugs in COVID-19 patients. 509

Another clinical trial started on May 8, 2020 exploiting a medical spray containing curcumin (20 mg/ml), 510 artemisinin (6 mg/ml), frankincense (15 mg/ml) -and vitamin C (60 mg/ml) in micellar formulation against 511 SARS-CoV2 infections (Table S1 ). 512

Moreover, on May 19th a clinical trails (NCT04394182) on patients affected by COVID-19 has started. In this 513 trial, an experimental group with a poor or no response to standard medical treatment and without 514 invasive mechanical ventilation are planned to receive an ultra low-dose lung radiotherapy (0.8 Gy single 515 dose) in addiction with different drugs (including Piperacillin/tazobactam). 516

Furthermore, a clinical trial started on March 5 (NCT04308317), planned to combine the use of the 517 tetrandrine (60 mg once a day), in tablets form, with the standard treatment of mild and severe neo-518 coronary pneumonia. The aim is the slowing down the progress of the disease and therefore the 519 improvement of patients' prognosis. All the information on these ongoing effots is crosslinked with our 520 collection in Table S1 . 521 522 Discussion 523

Despite advances in prevention, immunotherapy and drug development, some infectious diseases still 524 require effective vaccines or efficient antiviral therapies. As an example, coronaviruses, including SARS-525

CoV2 (Zhou et al., 2020) , that is causing the current pandemic disease, COVID19, as well as the other two 526 epidemic coronaviruses, SARS (Rota et al., 2003) and MERS (Zaki et al., 2012) , together with other 527 coronaviruses, do not have suitable therapies or preventive treatments yet (Sanders et al., 2020) . 528 Therefore, the identification of appropriate antiviral effectors for drugs and food design is of fundamental 529 importance to fight the COVID19 disease and all its side effects, to be ready for possible future challenges 530 that can be determined by coronaviruses attacks (Osterholm, 2005) . 531

Natural products (NPs) are compounds found in nature and synthesized by living organisms, that can be 532 revealed to be potential bioactive compounds useful in drug discovery and food sciences ( We performed a desk research and identified all natural compounds that appeared to inhibit human 539 coronaviruses infections, as revealed by in vitro experiments, or predicted by in silico analyses (Table S1 ). 540

Collecting information from several different reports, we selected the compounds that met the criteria of 541 being natural, not chemically modified substances, and of being effective on one or more phases 542 determining viral absorption and replication ( Figure 1) We merged all the compounds from different species, or eventually active on different phases, or selected 546 from different scientific efforts, into a unique list of 174 natural products, indicating all the relevant 547 information and annotating the specific targets according to the viral replication cycle, when known, as well 548

as the compound chemical classification (Table S1) . 549

The compounds resulted to be all from plants, with the exception of framycetin and sinefungin from 550

Streptomyces. All compounds were classified to be secondary metabolites, with major classes being 551

represented by Flavonoids (48 compounds), Terpenes (32 compounds), Xanthenes (13 compounds), 552

Alkaloids (9 compounds), Quinones (2 compounds). 553

In Figure 2 , we summarized the total amount of different classes per viral life cycle phase, also highlighting 554 the classes representing the compounds acting on multiple phases (Figure 2 ). It is evident that no active 555 compounds were revealed for phases 2 (release of viral genome) and 3 (translation of polyproteins). All the 556 details on specific compounds can be derived from Table S1 or consulting the website we organized to  557 share the data in a user friendly accessible resource (https://bigdatainhealth.org/letsbe/anti-HCoV.php). 558

Among the different phases, as an example, phase 1 (receptor binding and viral entry) is the most critical 559

for the overall infective process (Figure 1 ). Among the different events that occur in this phase, we could 560 find compounds that inhibit the Spike protein on the virus coat from interacting with the host receptor on 561 the human cell membrane. Most representative classes acting against this phase are: Terpenes (3), 562

Quinones (2) and Flavonoids (1) (Figure 2 and Table S1 ). Chrysin were detected to be active in this phase but also on the autoproteolytic activation (phase 4) ( Table S1) . 565

Harmonyl, an alkaloid, appeared to be the only compound that could act on phase 1 and also on other two 566 phases: the autoproteolytic activation and the genomic RNA replication. This action was revealed by an in 567 silico prediction (L. Zhang et al., 2020) and, therefore, further experiment could reveal the effective multi 568 target action of harmonyl against viral replication. 569

All the remaining compounds and target phases can be further investigated considering Table S1, in which  570 we also indicated links to the ClinicalTrial.gov (https://clinicaltrials.gov/), to provide information on 571 compounds under clinical trials. For a friendly consulting and further investigations, all the compounds here 572 described, endowed with the respective accessory information, are available also through anti-HCoVS, a 573 dedicated web based resource, available at https://bigdatainhealth.org/letsbe/anti-HCoV.php. This 574 resource was designed to offer a comprehensive collection of natural compounds that resulted effective 575 against human coronaviruses. The goal was to define a collection of natural compounds documented to be 576 effective in coronaviruses absorption and replication. All data can be friendly searchable and all references 577 are also crosslinked to the respective journal website. Moreover, compounds that can have multiple 578 purposes can be easily identified, supporting validation of possible efficacy on multiple targets, but also to 579 proof specificity of action. 580 581

We launched antiHCoV as a reference collection of natural compounds to be exploited against 583 coronaviruses epidemics. 584

While expanding the collection to consider the host side perspective, the current resource aimed to collect 585 all known compounds effective for natural treatments and proper food selection and design because of 586 their action against viral absorption and replication. We annotated those that were in vitro tested and 587 those predicted by computational analysis. We highlighted the action in the different viral life cycle phases 588 also to identify compounds that could inhibit the absorption, since this is one of the major target that could 589

help to fight the current and prevent the possible future coronaviral infections. 590

We aim to expand this collection with additional information on future results from novel testing and trials, 591

enriching the dataset with more upcoming compounds, also relying on a possible community based 592 support. 593 594 Acknowledgments 595 Emanuale Palomba is supported by a PhD fellowship founded by Stazione Zoologica Anton Dohrn and by 596 the NOSELF s.r.l (https://www.noself.it/). 597

Francesco Monticolo is supported by a PhD fellowship founded by the Department of Agricultural Sciences, 598

Università degli studi di Napoli Federico II. 599

University students under thesis gave their useful contribution to this community based collaborative effort 600 with enthusiasm and this is why they are considered co-authors in the effort. 601 602

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-604 profit sectors. 605 606 J o u r n a l P r e -p r o o f

The safety and regulation of natural products used as foods 610 and food ingredients

Evidence for camel-to-human transmission of MERS coronavirus

Anti-HIV-1 activity and structure-activity 616 relationship of cepharanoline derivatives in chronically infected cells

Resveratrol 620 inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and 621 radiosensitization in head and neck tumor cells

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A Cinnamon-Derived Procyanidin Compound 667

Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate-and Co-Receptor-Binding Sites on gp120 668 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation

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SARS and MERS: recent insights into 676 emerging coronaviruses

Adverse drug reactions: definitions, diagnosis, and management

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Resveratrol inhibits the hedgehog signaling pathway and 684 epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis

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Resveratrol inhibits hypoxia-driven ROS-induced invasive 735 and migratory ability of pancreatic cancer cells via suppression of the Hedgehog signaling pathway

Quercetin, Inflammation 741 and Immunity

Antiviral natural products and herbal medicines

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Resveratrol inhibits mTOR signaling by targeting DEPTOR

Antagonizes Antimicrobial Lethality and Stimulates Recovery of Bacterial Mutants

2 -Synthetic approaches of naturally and rationally designed 763 peptides and peptidomimetics

The Genus Phyllanthus: An Ethnopharmacological

Evidence-Based Complementary and Alternative 769 Medicine : ECAM

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Concordance of the toxicity of 775 pharmaceuticals in humans and in animals

Anti-inflammatory and anticancer 778 drugs from nature

Plant-derived natural products: Synthesis, function, and application 781

Preparing for the next pandemic

Bioactive Compounds and Properties of Seaweeds-A Review

Diarylheptanoids 787 from Alnus japonica Inhibit Papain-Like Protease of Severe Acute Respiratory Syndrome Coronavirus

Evaluation 790 of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

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Cleistocaltones A and B, Antiviral Phloroglucinol-Terpenoid Adducts from 841 Cleistocalyx operculatus

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Exploitation of Aspergillus terreus for the Production of 847

Yeast-849 based assays for the high-throughput screening of inhibitors of coronavirus RNA cap guanine-N7-850 methyltransferase

Terpenoids 852 from Croton regelianus

Suppression of nitric oxide synthase and the down-regulation 855 of the activation of NFkappaB in macrophages by resveratrol

Nutraceuticals and Natural Product Derivatives in the 858 Premises of Disease Prevention

Pharmacology of polymyxins: new 861 insights into an "old" class of antibiotics

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Swertia kouitchensis with α-glucosidase inhibitory activity

Fangchinoline inhibits human immunodeficiency virus 867 type 1 replication by interfering with gp160 proteolytic processing

Bats, civets and the emergence of SARS

Structure of MERS-CoV spike receptor-binding domain complexed 873 with human receptor DPP4

Small molecules 876 targeting severe acute respiratory syndrome human coronavirus

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by 881 computational methods

Fusion 884 mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein

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Saudi Arabia. The New England Journal 897 of Medicine

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