scholarly journals Lopinavir-ritonavir is not an effective inhibitor of the main protease activity of SARS-CoV-2 in vitro

2020 ◽  
Author(s):  
Minsu Jang ◽  
Yea-In Park ◽  
Rackhyun Park ◽  
Yeo-Eun Cha ◽  
Sim Namkoong ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Candidate Selection ◽  
Hiv Protease ◽  
Drug Candidate ◽  
Effective Inhibitor ◽  
Clinical Tests ◽  
Main Protease ◽  
Selection For

ABSTRACTCOVID-19 has caused over 900,000 deaths worldwide as of September 2020, and effective medicines are urgently needed. Lopinavir was identified as an inhibitor of the HIV protease, and a lopinavir-ritonavir combination therapy was reported to be beneficial for the treatment of SARS and MERS. However, recent clinical tests could not prove that lopinavir-ritonavir therapy was an effective treatment for COVID-19. In this report, we examined the effect of lopinavir and ritonavir to the activity of the purified main protease (Mpro) protein of SARS- CoV-2, the causative virus of COVID-19. Unexpectedly, lopinavir and ritonavir did not inhibit Mpro activity. These results will aid the drug candidate selection for ongoing and future COVID-19 clinical trials.

scholarly journals Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

2020 ◽  
Author(s):  
Abhisek Mishra ◽  
Sobha Chnadra Rath ◽  
Iswar Baitharu ◽  
Bhawani Prasad Bag
Keyword(s):  
Drug Target ◽  
Hiv Protease ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Major Health ◽  
Main Protease ◽  
Negative Effect ◽  
Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (M<sup>pro</sup>) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein M<sup>pro</sup>. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 M<sup>pro</sup> and may be further investigated to test its anti-viral activities using <i>in-vitro</i> and <i>in-vivo</i> study.

scholarly journals IDentif.AI: Artificial Intelligence Pinpoints Remdesivir in Combination with Ritonavir and Lopinavir as an Optimal Regimen Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

2020 ◽  
Author(s):  
Agata Blasiak ◽  
Jhin Jieh Lim ◽  
Shirley Gek Kheng Seah ◽  
Theodore Kee ◽  
Alexandria Remus ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Severe Acute Respiratory Syndrome ◽  
Combination Therapy ◽  
Rapid Development ◽  
Drug Combinations ◽  
Drug Candidate ◽  
Optimal Drug ◽  
Order Of Magnitude ◽  
Drug Regimens

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) has led to the rapid initiation of urgently needed clinical trials of repurposed drug combinations and monotherapies. These regimens were primarily relying on mechanism-of-action based selection of drugs, many of which have yielded positive in vitro but largely negative clinical outcomes. To overcome this challenge, we report the use of IDentif.AI, a platform that rapidly optimizes infectious disease (ID) combination therapy design using artificial intelligence (AI). In this study, IDentif.AI was implemented on a 12-drug candidate therapy search set representing over 530,000 possible drug combinations. IDentif.AI demonstrated that the optimal combination therapy against SARS-CoV-2 was comprised of remdesivir, ritonavir, and lopinavir, which mediated a 6.5-fold improvement in efficacy over remdesivir alone. Additionally, IDentif.AI showed hydroxychloroquine and azithromycin to be relatively ineffective. The identification of a clinically actionable optimal drug combination was completed within two weeks, with a 3-order of magnitude reduction in the number of tests typically needed. IDentif.AI analysis was also able to independently confirm clinical trial outcomes to date without requiring any data from these trials. The robustness of the IDentif.AI platform suggests that it may be applicable towards rapid development of optimal drug regimens to address current and future outbreaks.

scholarly journals Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

2020 ◽  
Author(s):  
Abhisek Mishra ◽  
Sobha Chnadra Rath ◽  
Iswar Baitharu ◽  
Bhawani Prasad Bag
Keyword(s):  
Drug Target ◽  
Hiv Protease ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Major Health ◽  
Main Protease ◽  
Negative Effect ◽  
Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (M<sup>pro</sup>) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein M<sup>pro</sup>. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 M<sup>pro</sup> and may be further investigated to test its anti-viral activities using <i>in-vitro</i> and <i>in-vivo</i> study.

scholarly journals Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models

Cell Research ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Gan Wang ◽  
Meng-Li Yang ◽  
Zi-Lei Duan ◽  
Feng-Liang Liu ◽  
Lin Jin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spike Protein ◽  
Drug Candidate ◽  
Peptide Drug ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Plasma Half Life

AbstractInfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8–10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.

Strategy of Utilizing In Vitro and In Vivo ADME Tools for Lead Optimization and Drug Candidate Selection

2005 ◽  
Vol 5 (11) ◽  
pp. 1033-1038 ◽  
Author(s):  
Suresh Balani ◽  
Gerald Miwa ◽  
Liang-Shang Gan ◽  
Jing-Tao Wu ◽  
Frank Lee
Keyword(s):  
Lead Optimization ◽  
Candidate Selection ◽  
Drug Candidate

scholarly journals Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

2020 ◽  
Author(s):  
mohamed mahdi ◽  
János András Mótyán ◽  
Zsófia Ilona Szojka ◽  
Mária Golda ◽  
Márió Miczi ◽  
...  
Keyword(s):  
Cell Culture ◽  
Protease Inhibitors ◽  
Significant Inhibition ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
High Concentration ◽  
Viral Protease ◽  
Main Protease ◽  
Depth Analysis

Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. Atazanavir on the other hand was the only PI to inhibit the viral protease both in cell culture and in our in vitro enzymatic assay. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

scholarly journals HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

2020 ◽  
Author(s):  
Marcelo Freitas Montenegro ◽  
Yousef Al-Abed ◽  
Mingzhu He ◽  
Kevin J. Tracey ◽  
Timothy R. Billiar
Keyword(s):  
Clinical Trials ◽  
Cathepsin L ◽  
Inhibitory Effect ◽  
Host Cells ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Potential Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a drug-based treatment for its control. Cathepsin L is an endosomal cysteine protease that mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells and viruses/host cell endosome membrane fusion. Therefore, cathepsin L is a potential target for the treatment of COVID-19 patients. In this report, we describe a previously unknown inhibitory effect of two FDA-approved drugs, saquinavir and nelfinavir, on human cathepsin L activity. Whether the pivotal role for cathepsin L in Sars-Cov-2 infection described in vitro can be translated to humans, our results support immediate clinical trials of saquinavir or nelfinavir as a potential treatment for COVID-19 patients.

An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study

2020 ◽  
Author(s):  
Sourav Das ◽  
Sharat Sarmah ◽  
Sona Lyndem ◽  
Atanu Singha Roy
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Active Site ◽  
Natural Compound ◽  
World Health ◽  
Molecular Docking Study ◽  
Control Drug ◽  
Main Protease

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under <i>in vitro</i> as well as <i>in vivo </i>conditions.

An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study

2020 ◽  
Author(s):  
Sourav Das ◽  
Sharat Sarmah ◽  
Sona Lyndem ◽  
Atanu Singha Roy
Keyword(s):  
Clinical Trials ◽  
Molecular Docking ◽  
Active Site ◽  
Natural Compound ◽  
World Health ◽  
Molecular Docking Study ◽  
Control Drug ◽  
Main Protease

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under <i>in vitro</i> as well as <i>in vivo </i>conditions.

scholarly journals Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2′s main protease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Mohamed Mahdi ◽  
János András Mótyán ◽  
Zsófia Ilona Szojka ◽  
Mária Golda ◽  
Márió Miczi ◽  
...  
Keyword(s):  
Cell Culture ◽  
Protease Inhibitors ◽  
Significant Inhibition ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Viral Protease ◽  
Enzymatic Assays ◽  
Main Protease ◽  
Depth Analysis

Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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