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Fundamental and Clinical Pharmacology ; 36:17, 2022.
Article in English | EMBASE | ID: covidwho-1968103


Introduction: The urgency of finding effective treatments for severe forms of COVID-19 has necessitated adaptations to clinical trial designs. Almost all of the initial randomized trials had to be open-label and placebo-free. We were able to seize the opportunity to conduct a double-blind placebo-controlled trial by integrating ourselves into an ongoing trial and offer here some lessons from this experience. Material and methods: The CAPE-COD trial (NCT 02517489) sought to show a decrease in day 28 mortality in patients admitted to critical care with community-acquired pneumonia and receiving hydrocortisone compared with placebo. The inclusion of patients with COVID-19 was possible but required urgent responses to several problems: i) choose between subgroup analysis or segregation of COVID patients from others;ii) simultaneously include in both trials or discontinue the parent trial;iii) adapt methods to achieve a rapid response, including changing the primary endpoint;iv) define the maximum size and stopping boundaries of a sequential trial in the absence of solid data on disease progression;v) quickly obtain ethical and regulatory approvals and funding;vi) conduct the trial in overcrowded centers;vii) not jeopardize the rigor of the parent trial despite an interruption in its recruitment [1]. These elements will be discussed orally. Results: 150 patients were included before the DSMB suggested that inclusions be stopped due to the pre-publication of RECOVERY. Hydrocortisone did not significantly reduce the primary endpoint, treatment failure (defined as death or persistent respiratory support) at day 21, but a post-hoc analysis showed that relative mortality at day 21 was 46% lower (14.7 vs. 27.4%) with hydrocortisone compared to placebo, a non-significant difference (p = 0.057) but with an effect size comparable to that observed in RECOVERY. Tolerance was good [2]. Discussion/Conclusion: The rapid response to many methodological problems allowed a trial with low risk of bias to be conducted despite the pandemic pressure.

J Biomol Struct Dyn ; 40(1): 1-13, 2022 01.
Article in English | MEDLINE | ID: covidwho-436584


Coronavirus disease 2019 (COVID-19) initiated in December 2019 in Wuhan, China and became pandemic causing high fatality and disrupted normal life calling world almost to a halt. Causative agent is a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV). While new line of drug/vaccine development has been initiated world-wide, in the current scenario of high infected numbers, severity of the disease and high morbidity, repurposing of the existing drugs is heavily explored. Here, we used a homology-based structural model of transmembrane protease serine 2 (TMPRSS2), a cell surface receptor, required for entry of virus to the target host cell. Using the strengths of molecular docking and molecular dynamics simulations, we examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) and caffeic acid phenethyl ester to TPMRSS2 in comparison to its known inhibitor, Camostat mesylate. We found that both Wi-A and Wi-N could bind and stably interact at the catalytic site of TMPRSS2. Wi-N showed stronger interactions with TMPRSS2 catalytic residues than Wi-A and was also able to induce changes in its allosteric site. Furthermore, we investigated the effect of Wi-N on TMPRSS2 expression in MCF7 cells and found remarkable downregulation of TMPRSS2 mRNA in treated cells predicting dual action of Wi-N to block SARS-CoV-2 entry into the host cells. Since the natural compounds are easily available/affordable, they may even offer a timely therapeutic/preventive value for the management of SARS-CoV-2 pandemic. We also report that Wi-A/Wi-N content varies in different parts of Ashwagandha and warrants careful attention for their use.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2 , Serine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects , Withanolides/pharmacology , Binding Sites , COVID-19 , Humans , MCF-7 Cells , Molecular Docking Simulation , Plant Extracts/chemistry , Serine , Serine Endopeptidases/genetics
J Biomol Struct Dyn ; 39(11): 3842-3854, 2021 07.
Article in English | MEDLINE | ID: covidwho-324383


The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, Mpro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 Mpro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.Communicated by Ramaswamy H. Sarma.

COVID-19 , SARS-CoV-2 , Caffeic Acids , Humans , Molecular Docking Simulation , Peptide Hydrolases , Phenylethyl Alcohol/analogs & derivatives , Protease Inhibitors/pharmacology , Withanolides