Stereoselective and regioselective Heck arylation at C-17 exocyclic double bond of andrographolide to generate labdane-based lead molecule against acute lung injury

Andrographolide (AG-1) is identified as an attractive scaffold based on in silico/in vitro/in vivo (preclinical and clinical) studies against COVID-19 infection, for which hardly any effective drug is available to date. Due to complexity of its chemical structure, stereoselective and regioselective Heck arylation reactions at C-17 exocyclic double bond of AG-1 is a major challenge and we stepped forward to generate a small focused library of compounds. Among all the molecules, AG-12 and AG-13 were predicted to have better pharmacokinetic profiles than AG-1. Upon evaluation of in vivo efficacy of AG-12 and AG-13 in comparison to AG-1 using an LPS-induced acute lung injury model, AG-13 showed promising action towards reduction of the neutrophil count, minimization of oxidative stress, and inhibition of inflammatory cytokines. Further, lead optimization should be carried out towards developing potential natural product-driven therapeutics to combat acute respiratory distress syndrome (ARDS) situations during COVID-19. © 2023 Elsevier B.V.

In Silico Analysis of 14-Deoxy 11, 12-Didehydro Andrographolide (AGP 2) From Sambiloto (Andrographis paniculata) As Drug Candidate Against SARS-CoV-2

The outbreak of the COVID-19 pandemic in the world has urged researchers to develop a vaccine or therapeutic drugs to fight this virus. This study aimed to assay 14 deoxy-11,12-didehydroandrographolide (AGP 2) ability as an inhibitor of 3-chymotrypsin like-protease (3CLPro), Papain-like protease (PLPro), and RNA-dependent RNA-polymerase (RdRp), the viral proteins of SARS-CoV-2 and to evaluate it safeness as a drug candidate. In-silico technique was performed in this study to analyze the binding interaction, complex stability between protein and ligand, and drug-likeness properties. The proteins and ligands were obtained from Protein Data Bank (PDB) and PubChem web tools, then using PyRx to identify the binding affinity score, PyMoL to visualize the 3D binding interaction, and WebGro web tools to analyze the stability of each complex. A drug-likeness evaluation was done using SwissADME, pkCSM, and Way2drug web tools. The result of this study showed that the binding affinity score for each complex is;AGP 2-3CLPro (-6.7 kcal/mol), AGP 2-PLPro (-6.4 kcal/mol), and AGP 2-RdRp (-7.0 kcal/mol) where the AGP 2-RdRp and AGP 2-3CLPro showed a stable form indicating the inhibitor ability of AGP 2. This study also demonstrates that the drug-likeness properties of AGP 2 are safe to use. Additionally, it has been proved that AGP 2 can be developed into a therapeutic drug with further studies. © 2023, Bogor Agricultural University. All rights reserved.

Perspective: repurposed drugs for COVID-19.

Introduction: The article aims to emphasize the necessity of proper research design, both scientifically and ethically, in order to provide good evidence for physicians to base their decisions on when prescribing drug treatment. Methods: Research articles and guidelines related to therapy of COVID-19 were searched from the PubMed database. Results: Only remdesivir and tocilizumab are medicines that have been approved by the US FDA's decision to approve their clinical use in moderate and severe COVID-19. Conclusions: Favipiravir, ivermectin and andrographolide need further well-conducted research to confirm the efficacy and safety against COVID-19 at different stages.

In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment.

Andrographolide (APE) has been used for COVID-19 treatment in various clinical settings in South-East Asia due to its benefits on reduction of viral clearance and prevention of disease progression. However, the limitation of APE clinical use is the high incidence of adverse events. The objective of this study was to find the optimal dosage regimens of APE for COVID-19 treatment. The whole-body physiologically-based pharmacokinetic (PBPK) models were constructed using data from the published articles and validated against clinical observations. The inhibitory effect of APE was determined for the potency of drug efficacy. For prevention of pneumonia, multiple oral doses such as 120[Formula: see text]mg for three doses, followed by 60[Formula: see text]mg three times daily for 4 consecutive days, or 200[Formula: see text]mg intravenous infusion at the rate of 20 mg/h once daily is advised in patients with mild COVID-19. For prevention of pneumonia and reduction of viral clearance time, the recommended dosage regimen is 500[Formula: see text]mg intravenous infusion at the rate of 25[Formula: see text]mg/h once daily in patients with mild-to-moderate COVID-19. One hundred virtual populations (50 males and 50 females) were simulated for oral and intravenous infusion formulations of APE. The eligible PBPK/PD models successfully predicted optimal dosage regimens and formulations of APE for prevention of disease progression and/or reduction of viral clearance time. Additionally, APE should be co-administered with other antiviral drugs to enhance therapeutic efficacy for COVID-19 treatment.

The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics.

The current coronavirus disease 2019 (COVID-19) outbreak is alarmingly escalating and raises challenges in finding efficient compounds for treatment. Repurposing phytochemicals in herbs is an ideal and economical approach for screening potential herbal components against COVID-19. Andrographis paniculata, also known as Chuan Xin Lian, has traditionally been used as an anti-inflammatory and antibacterial herb for centuries and has recently been classified as a promising herbal remedy for adjuvant therapy in treating respiratory diseases. This study aimed to screen Chuan Xin Lian's bioactive components and elicit the potential pharmacological mechanisms and plausible pathways for treating COVID-19 using network pharmacology combined with molecular docking. The results found terpenoid (andrographolide) and flavonoid (luteolin, quercetin, kaempferol, and wogonin) derivatives had remarkable potential against COVID-19 and sequelae owing to their high degrees in the component-target-pathway network and strong binding capacities in docking scores. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the PI3K-AKT signaling pathway might be the most vital molecular pathway in the pathophysiology of COVID-19 and long-term sequelae whereby therapeutic strategies can intervene.

Whole transcriptome analysis identifies full-length genes for neoandrographolide biosynthesis from Andrographis alata, an alternate source for antiviral compounds.

Andrographolide and related compounds are effective against several viral diseases, including dengue, COVID-19, influenza, and chikungunya. Andrographis paniculata is the primary source for these compounds, but its availability is limited. A. alata is a potential alternative source, and neoandrographolide (NAG) is the major antiviral compound in this species. Since molecular studies in A. alata are scarce, we sequenced its leaf transcriptome to identify the full-length genes involved in neoandrographolide biosynthesis. We assembled 13.6 Gb RNA-Seq data and generated 81,361 transcripts with 1007 bp average length and 1,810 bp N50. The transcripts were categorized under biological processes (2,707), cellular components (678), and molecular functions (2,036). KEGG analysis mapped 975 transcripts to the secondary metabolite pathways. Among the 420 transcripts mapped to terpenoids and polyketides pathways, 142 transcripts were related to the biosynthesis of andrographolide and its derivatives. After a detailed analysis of these transcripts, we identified 32 full-length genes coding for all the 22 enzymes needed for andrographolide biosynthesis. Among them, 15 full-length genes were identified for the first time from Andrographis species. These full-length genes and the transcripts shall serve as an invaluable resource for the metabolic engineering of andrographolides and neoandrographolide in Andrographis and other species.

A comprehensive review on disposition kinetics and dosage of oral administration of Andrographis paniculata, an alternative herbal medicine, in co-treatment of coronavirus disease.

Coronavirus disease 2019 (COVID-19) is a present global health crisis that is driving the investigation of alternative phytomedicines for antiviral purposes. The evidence suggests that Andrographis paniculata crude or extract is a promising candidate for treating symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review aims to consolidate the available reports on the disposition kinetics of andrographolide, a main active component of A. paniculata. The second objective of this review is to summarize the available reports on an appropriate oral dosage for the use of andrographolide in upper respiratory tract infections (URTIs) and other viral infectious diseases. The data were collected from the literature on absorption, distribution, biotransformation, and excretion of andrographolide, and information was also obtained from scientific databases about the use of A. paniculata. The finding of this review on pharmacokinetics indicates that andrographolide is slightly absorbed into the blood circulation and exhibits poor oral bioavailability, whereas its distribution process is unrestricted. In the termination phase, andrographolide preferentially undergoes biotransformation partly through phase I hydroxylation and phase II conjugation, and it is then eliminated via the renal excretion and hepatobiliary system. The key summary of the recommended dosage for andrographolide in uncomplicated URTI treatment is 30 mg/day for children and 60 mg/day for adults. The dose for adult patients with pharyngotonsillitis could be increased to 180 mg/day, but not exceed 360 mg/day. Co-treatment with A. paniculata in concert with the standard supportive care for influenza reduced the severity of symptoms, shortened treatment duration, and decreased the risk of developing post-influenza complications. The recommended starting dose for use in patients with mild COVID-19 is 180 mg/day of andrographolide, based on the dose used in patients experiencing a URTI with inflammation. This review is not only applicable for evaluating the appropriate doses of andrographolide for antiviral treatments but also encourages future research evaluating the effectiveness of these recommended dosages during the COVID-19 pandemic.

Use of Andrographis paniculata (Burm.f.) Wall. ex Nees and risk of pneumonia in hospitalised patients with mild coronavirus disease 2019: A retrospective cohort study.

Background: Andrographis paniculata (Burm.f.) Wall. ex Nees (AP) has been widely used in Thailand to treat mild COVID-19 infections since early 2020; however, supporting evidence is scarce and ambiguous. Thus, this study aimed to examine whether the use of AP is associated with a decreased risk of pneumonia in hospitalised mild COVID-19 patients. Materials and methods: We collected data between March 2020 and August 2021 from COVID-19 patients admitted to one hospital in Thailand. Patients whose infection was confirmed by real-time polymerase chain reaction, had normal chest radiography and did not receive favipiravir at admission were included and categorised as either AP (deriving from a dried and ground aerial part of the plant), given as capsules with a total daily dose of 180 mg andrographolide for 5 days or standard of care. They were followed for pneumonia confirmed by chest radiography. Multiple logistic regression was used for the analysis controlling for age, sex, diabetes, hypertension, statin use, and antihypertensive drug use. Results: A total of 605 out of 1,054 patients (mostly unvaccinated) were included in the analysis. Of these, 59 patients (9.8%) developed pneumonia during the median follow-up of 7 days. The incidence rates of pneumonia were 13.93 (95% CI 10.09, 19.23) and 12.47 (95% CI 8.21, 18.94) per 1,000 person-days in the AP and standard of care groups, respectively. Compared to the standard of care group, the odds ratios of having pneumonia in the AP group were 1.24 (95% CI 0.71, 2.16; unadjusted model) and 1.42 (95% CI 0.79, 2.55; fully adjusted model). All sensitivity analyses were consistent with the main results. Conclusion: The use of AP was not significantly associated with a decreased risk of pneumonia in mild COVID-19 patients. While waiting for insights from ongoing trials, AP's use in COVID-19 should be done with caution.

The use of andrographolide and effects on liver biochemistry in patients with gastrointestinal problems amid the pandemic of COVID-19

Objectives: In the situation of COVID-19 pandemic in Thailand, healthcare facility supply and access are limited. There was an announcement promoting Andrographolide (ADG) use in treatment of mild COVID-19 patients, but misconception of taking for prevention might occur. Moreover, the effect of ADG on liver function test (LFT) has not been established. We aim to study the prevalence of ADG use and effect on LFTs in patients with gastrointestinal (GI) problems. Materials and Methods: We conducted a cross-sectional study including GI patients at our center who voluntarily filled the ADG questionnaire in Aug-Sep 2021. LFT data at that visit and at the prior visit (if available) were obtained. The changes in LFT within the same person were analyzed using Wilcoxon signed-rank test. Wilcoxon rank-sum and Chi-square test were used to compare between patients with and without ADG consumption. Results: A total of 886 patients completed the survey, 170 patients (19.2%) took ADG within the past month. Patients who took ADG were more likely to have history of COVID-19 infection in their closed companies (5.6% vs 1.5%) compared with who did not (control group). LFT data were available in 486 (54.8%) patients, the median ALT change compared with the prior visit was higher in ADG vs control group (2 vs 0, p = 0.026), and 45% had increased ALT ([3 U/L) vs 32.2% in ADG and control group, respectively (p = 0.023). Multivariable logistic regression analysis found that factors independently associated with an increased ALT were ADG exposure (adjusted OR [aOR] of 1.62, p = 0.042), and patients with NAFLD who gained weight (aOR of 2.37, p = 0.046). Conclusion: One-fifth of GI patients recently took ADG, in which currently not indicated as it has no effect on preventing COVID-19 infection. Those who took ADG are more likely to experience an increase in ALT than who did not. Warning should be made regarding this issue.

Andrographolide and Deoxyandrographolide Inhibit Protease and IFN-Antagonist Activities of Foot-and-Mouth Disease Virus 3Cpro.

Foot-and mouth-disease (FMD) caused by the FMD virus (FMDV) is highly contagious and negatively affects livestock worldwide. The control of the disease requires a combination of measures, including vaccination; however, there is no specific treatment available. Several studies have shown that plant-derived products with antiviral properties were effective on viral diseases. Herein, antiviral activities of andrographolide (AGL), deoxyandrographolide (DAG), and neoandrographolide (NEO) against FMDV serotype A were investigated using an in vitro cell-based assay. The results showed that AGL and DAG inhibited FMDV in BHK-21 cells. The inhibitory effects of AGL and DAG were evaluated by RT-qPCR and exhibited EC50 values of 52.18 ± 0.01 µM (SI = 2.23) and 36.47 ± 0.07 µM (SI = 9.22), respectively. The intracellular protease assay revealed that AGL and DAG inhibited FMDV 3Cpro with IC50 of 67.43 ± 0.81 and 25.58 ± 1.41 µM, respectively. Additionally, AGL and DAG significantly interfered with interferon (IFN) antagonist activity of the 3Cpro by derepressing interferon-stimulating gene (ISGs) expression. The molecular docking confirmed that the andrographolides preferentially interacted with the 3Cpro active site. However, NEO had no antiviral effect in any of the assays. Conclusively, AGL and DAG inhibited FMDV serotype A by interacting with the 3Cpro and hindered its protease and IFN antagonist activities.

A New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm.

Cytokine storm is a condition in which the immune system produces an excessive number of inflammatory signals, which can result in organ failure and death. It is also known as cytokine release syndrome, CRS, or simply cytokine storm, and it has received a lot of attention recently because of the COVID-19 pandemic. It appears to be one of the reasons why some people experience life-threatening symptoms from COVID-19, a medical condition induced by SARS-CoV-2 infection. In situations where natural substances can be exploited as therapeutics to reduce cytokine storm, the drug development process has come to the rescue. In the present study, we tested the potentiality of Andrographolide, labdane diterpenoid targeting several key cytokines that are secreted as a result of cytokine storm. We used molecular docking analyses, molecular dynamics simulations, and pharmacokinetic properties to test the stability of the complexes. The compound's binding energy with some cytokines was over -6.5 Kcal/mol. Furthermore, a post-molecular dynamics (MD) study revealed that Andrographolide was extremely stable with these cytokines. The compound's pharmacokinetic measurements demonstrated excellent properties in terms of adsorption, distribution, metabolism, and excretion. Our research revealed that this compound may be effective in lowering cytokine storm and treating severe symptoms.

Andrographolide induces anti-SARS-CoV-2 response through host-directed mechanism: an in silico study.

Aim: Considering the present alarming situation of COVID-19 pandemic, we concentrated on evaluating the efficacy of a novel natural antiviral drug-candidate andrographolide against SARS-CoV-2 through an in silico model of study. Materials & methods: Interaction of andrographolide against the major host molecules that are responsible for SARS-CoV-2 pathogenesis were determined using bio-computational tools, in other words, molecular docking, molecular dynamics simulation and pharmacodynamics-pharmacokinetics analysis. Result: Computational findings represent that andrographolide efficiently interacts with the major human-host-associated putative drug-targets of viral-entry points like furin (-10.54 kcal/mol), TMPRSS-2 (-9.50 kcal/mol), ACE2 (-8.99 kcal/mol) and Cathepsin L (-8.98 kcal/mol). Moreover, it also blocks the inflammatory regulators including TLR4-MD2 and IL-6, which promote virus-induced inflammation leading to cytokine storm in the host body. Conclusion: This work elucidates that, the candidature of andrographolide can be utilized as a potent natural agent for the therapeutic intervention of SARS-CoV-2 through host-directed treatment.

The Development of a Physiologically Based Pharmacokinetic (PBPK) Model of Andrographolide in Mice and Scaling it up to Rats, Dogs, and Humans.

BACKGROUND: Andrographolide has a potent antiviral effect in the treatment of coronavirus disease (COVID-19). However, there are no in vivo studies of andrographolide as an anti-COVID-19 treatment. OBJECTIVE: The study aims to develop a physiologically based pharmacokinetic (PBPK) animal model and scale it up to a human model to predict andrographolide concentrations in the lungs. METHODS: ADAPT5 (version 5.0.58) was used to establish the PBPK model based on 24 enrolled pharmacokinetic studies. RESULTS: The perfusion-limited PBPK model was developed in mice and extrapolated to rats, dogs, and humans. The metabolism of andrographolide in humans was described by the Michaelis-Menten equation. The saturation of the metabolism occurred at a high dose (12 g), which could not be used therapeutically. The optimized oral bioavailability in humans was 6.3%. Due to the limit of solubility, the dose-dependent absorption between 20-1000 mg was predicted by GastroPlus®. Using the extrapolated human PBPK model together with the predicted dose-dependent fraction of the dose absorbed that enters the enterocytes by GastroPlus®, the oral dosage of 200 mg q8h of andrographolide would provide a trough level of free andrographolide at a steady state over the reported IC50 value against SARS-CoV-2 in the lungs for the majority of healthy humans. Based on the reported CC50 value, toxicity might not occur at the therapeutic dosage. CONCLUSION: The PBPK model of andrographolide in animals and humans was successfully constructed. Once additional data is available, the model would be needed to recalibrate to gain an understanding of a dose-response relationship and optimization of dosage regimens of andrographolide.

Ayurveda and Siddha systems polyherbal formulations to treat COVID-19 caused by SARS-CoV-2 and brief insight on application of Molecular Docking and SWISS Target prediction tools to study efficacy of active molecules

Ayurveda and Siddha systems are the two ancient medical systems originated in India more than 4000 years ago had given many formulary and treatment methods against influenza like infections. Kabasura churan from Siddha system and Maha sudharshan churan from the Ayurvedic system are the two major formulations along with many other individual herbs mentioned in the texts to treat Influenza like infections. Kabasura churan and Maha Sudarshan churan both have antipyretic, analgesic and anti-inflammatory effects. Both formulations were prepared according to Siddha and Ayurvedic texts. Herbs mentioned in both formulations like Turmeric, Tulsi (Basil), Kalmegh (Andrographis), Black Pepper, Liquorice (Mulethi), and Dronapushpi (Leucas) etc., had direct antiviral effect. Herbs like Aswagandha, Ginger, Guduchi (Tinospora), Kulanjan (Galangal) etc., had immunomodulatory and anti-inflammatory effect. Active compounds from different herbs were selected to study their antiviral activity through molecular docking algorithm. Application of modern of tools like Bioinformatics and Highthroughput screening methods can predict the efficacy of the ancient documented formulations and can be compared as per their literature. Compounds like curcumin, Glycyrrhizin, Ursolic acid, Quercetin, Andrographolide, Coumarins etc. were showed polyspecific activity like inhibition of Spike protein, Furin, Main Protease (Mpro) and Papain like Proteases (PLpro). Thus we propose use of Kabasura churan and Maha Sudharshan churan as alternative complementary medicine as a palliative treatment against COVID-19 caused by SARS-CoV-2 by conducting proper Randomized Clinical Trials.

Advances in traditional Chinese medicine for respiratory disease therapy in 2021

Respiratory diseases are common conditions that endanger human health. Their etiology, pathogenesis, and prognosis are complex, and clinical research has been extensive. This paper reviews studies from the PubMed database to assess the progress of traditional Chinese medicine in the treatment of respiratory diseases in 2021, focusing on related animal and cell models of coronavirus disease 2019. Traditional Chinese medicine extracts, such as polysaccharides and emodin, and classic prescriptions, such as Mahuang decoction, respond to the treatment of influenza by reducing viral infections and regulating the body’s immune response. Chinese herbal extracts, such as schizandra B and andrographolide, treat asthma by inhibiting inflammatory response pathway formation, NLRP3 inflammasome formation, oxidative stress, and autophagy. Traditional Chinese medicine extracts such as fucoxanthin, and proprietary Chinese medicines such as the Xihuang pill is used in the treatment of lung cancer, as it regulates the cell cycle, inhibit tumor cell proliferation, and enhance the body’s immune function. Classic formulas such as the kidney tonic lung formula and proprietary Chinese medicine, such as compound grass stone silkworm granules, relieve airway inflammation and improve lung function in chronic obstructive pulmonary disease. Chinese herbal extracts, such as jostilbene and sage phenol, inhibit epithelial cell–mesenchymal transformation and regulate the levels of inflammatory factors to treat idiopathic pulmonary fibrosis to provide a reliable basis for the treatment of respiratory diseases.

Discovery of C-12 dithiocarbamate andrographolide analogues as inhibitors of SARS-CoV-2 main protease: In vitro and in silico studies.

A global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people's lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has become an urgent need to combat COVID-19. One of the most attractive drug targets for discovering anti-SARS-CoV-2 agents is the main protease (Mpro), which plays a pivotal role in the viral life cycle. This study aimed to elucidate a series of twenty-one 12-dithiocarbamate-14-deoxyandrographolide analogues as SARS-CoV-2 Mpro inhibitors using in vitro and in silico studies. These compounds were initially screened for the inhibitory activity toward SARS-CoV-2 Mpro by in vitro enzyme-based assay. We found that compounds 3 k, 3 l, 3 m and 3 t showed promising inhibitory activity against SARS-CoV-2 Mpro with >50% inhibition at 10 µM. Afterward, the binding mode of each compound in the active site of SARS-CoV-2 Mpro was explored by molecular docking. The optimum docked complexes were then chosen and subjected to molecular dynamic (MD) simulations. The MD results suggested that all studied complexes were stable along the simulation time, and most of the compounds could fit well with the SARS-CoV-2 Mpro active site, particularly at S1, S2 and S4 subsites. The per-residue decomposition free energy calculations indicated that the hot-spot residues essential for ligand binding were T25, H41, C44, S46, M49, C145, H163, M165, E166, L167, D187, R188, Q189 and T190. Therefore, the obtained information from the combined experimental and computational techniques could lead to further optimization of more specific and potent andrographolide analogues toward SARS-CoV-2 Mpro.

Identification of Potential Semisynthetic Andrographolide Derivatives to Combat COVID-19 by Targeting the SARS-COV-2 Spike Protein and Human ACE2 Receptor– An In-silico Approach

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causal factor for the current deadly infectious disease CoVID-19. There is no specific drug available for treating COVID-19 other than some vaccines approved for prevention. However, a lot of research is in progress to prove the anti-COVID-19 potential of natural and synthetic compounds. Objective: The present study was aimed to identify the anti-COVID-19 potential of andrographolide (AGP) derivatives by in-silico molecular interaction study. Seventeen AGP derivatives were screened for drug-likeness, ADME, and toxicity profile using in-silico online tools. Then the filtered AGP were subjected to molecular docking using the PyRx tool integrated with AutoDock Vina software. Compounds AGP 15, 14, and 10 have been identified as promising binding molecules for both S and ACE2, preventing the interaction between S and ACE2. AGP-15 had shown a −8.4 Kcal/mol binding/docking score for S, AGP-10 and 14 showed a-8.3 and-8.2 Kcal/mol binding/docking score for ACE2. Overall results indicated that AGP derivatives 15 and 14 might be the best candidates to battle COVID-19. However, further studies like dynamic molecular studies and pharmacological screenings are essential to confirm the stability and action potential of AGP derivatives 14 and 15 as a lead against COVID-19. © 2022 by the authors.

Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach.

BACKGROUND: The recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection cause high mortality and there is an emergency need to develop a specific drug to treat the novel coronavirus disease, COVID-19. However, some natural and synthetic products with action against SARS-CoV-2 have been reported in recent research, there is no specific drug available for treating COVID-19. In the present study, molecular interaction analysis was performed for 16 semisynthetic andrographolides (AGP) against 5 SARS-CoV-2 enzymes main protease (Mpro, PDB: 6LU7), papain-like protease (PLpro, PDB: 6WUU), spike glycoprotein (S, PDB: 6VXX), NSP15 endoribonuclease (NSP15, PDB: 6VWW), and RNA-dependent RNA polymerase (RdRp, PDB: 6M71). Moreover, the compounds pharmacokinetic and toxic profiles were also analyzed using computational tools. RESULTS: The protein-ligand docking score (kcal/mol) revealed that all the tested AGP derivatives showed a better binding affinity towards all the tested enzymes than hydroxychloroquine (HCQ). Meanwhile, all the tested AGP derivatives showed a better binding score with RdRp and S than remdesivir (REM). Interestingly, compounds 12, 14, and 15 showed a better binding affinity towards the all the tested enzyme than AGP, REM, and HCQ. AGP-16 had shown - 8.7 kcal/mol binding/docking score for Mpro, AGP-15 showed - 8.6 kcal/mol for NSP15, and AGP-10, 13, and 15 exhibited - 8.7, - 8.9, and - 8.7 kcal/mol, respectively, for S. CONCLUSION: Overall results of the present study concluded that AGP derivatives 14 and 15 could be the best 'lead' candidate for the treatment against SARS-CoV-2 infection. However, molecular dynamic studies and pharmacological screenings are essential to developing AGP derivatives 14 and 15 as a drug against COVID-19.

Front Cover: Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti-SARS-CoV-2 Activity (ChemMedChem 5/2022)

The Front Cover illustrates the natural product andrographolide, which modulates the abundance of the transcription factor NRF2, a substrate of the E3 ligase KEAP1. Previous studies identified that this drug possessed anti-SARS-CoV-2 activity, but the mechanism of action remained unclear. The authors designed and synthesized novel andrographolide derivatives with a functional site to fine-tune physicochemical properties and for linker attachment. The team assayed this new set of compounds in a cell-based NRF2 reporter gene assay and determined their ability to decrease infectivity of virus-treated Vero-E6 cells. Data showed that NRF2 activation by compounds and inhibition of SARS-CoV-2 replication correlated well. The study opens new avenues to investigate natural products that target the KEAP1/NRF2 axis as anti-SARS-CoV-2 agents. More information can be found in the Research Article by Christian Steinebach et al. 

Discovery of Novel Andrographolide Derivatives as Antiviral Inhibitors against Human Enterovirus A71.

Hand-foot-and-mouth disease (HFMD) caused by human enterovirus A71 (EV-A71) infection has been associated with severe neurological complications. With the lack of an internationally approved antiviral, coupled with a surge in outbreaks globally, EV-A71 has emerged as a neurotropic virus of high clinical importance. Andrographolide has many pharmacological effects including antiviral activity and its derivative, andrographolide sulfonate, has been used in China clinically to treat EV-A71 infections. This study sought to identify novel andrographolide derivatives as EV-A71 inhibitors and elucidate their antiviral mode of action. Using an immunofluorescence-based phenotypic screen, we identified novel EV-A71 inhibitors from a 344-compound library of andrographolide derivatives and validated them with viral plaque assays. Among these hits, ZAF-47, a quinolinoxy-andrographolide, was selected for downstream mechanistic studies. It was found that ZAF-47 acts on EV-A71 post-entry stages and inhibits EV-A71 protein expression. Subsequent luciferase studies confirm that ZAF-47 targets EV-A71 genome RNA replication specifically. Unsuccessful attempts in generating resistant mutants led us to believe a host factor is likely to be involved which coincide with the finding that ZAF-47 exhibits broad-spectrum antiviral activity against other enteroviruses (CV-A16, CV-A6, Echo7, CV-B5, CV-A24 and EV-D68). Furthermore, ZAF-46 and ZAF-47, hits from the screen, were derivatives of the same series containing quinolinoxy and olefin modifications, suggesting that an andrographolide scaffold mounted with these unique moieties could be a potential anti-EV-A71/HFMD strategy.