scholarly journals A Survey of Inhibitors for the Main Protease of Coronaviruses with the Potential for Development of Broad-Spectrum Therapeutics

2021 ◽  
Vol 17 (4) ◽  
pp. 71-84
Author(s):  
Alyssa Sanders ◽  
Samuel Ricci ◽  
Sarah Uribe ◽  
Bridget Boyle ◽  
Brian Nepper ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Active Site ◽  
Human Life ◽  
Neuraminidase Inhibitor ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors

The coronaviruses plaguing humanity in the 21st century share much in common: a spontaneous route of origin from wild animals, a propensity to take human life, and, importantly, a highly conserved set of biological machinery necessary for viral replication. Most recently, the SARS-CoV-2 is decimating economies around the world and has claimed over two million human lives, reminding the world of a need for an effective drug against present and future coronaviruses. To date, attempts to repurpose clinically approved antiviral medications show minimal promise, highlighting the need for development of new antiviral drugs. Nucleotide analog inhibitors are a promising therapeutic candidate, but early data from clinical studies suggests these compounds have limited efficacy. However, novel compounds targeting the main protease responsible for critical steps in viral assembly are gaining considerable interest because they offer the potential for broad-spectrum coronavirus therapy. Here, we review the literature regarding potential inhibitors for the main protease of coronaviruses, especially SARS-CoV-2, analyze receptor-drug interactions, and draw conclusions about candidate inhibitors for future outbreaks. Promising candidates for development of a broad-spectrum coronavirus protease inhibitor include the neuraminidase inhibitor 3K, the peptidomimetic inhibitor 11a and 11b, the α-ketoamide inhibitor 13b, the aldehyde prodrug, and the phosphate prodrug developed by Pfizer. In silico and in vitro analyses have shown that these inhibitors strongly interact with the active site of the main protease, and to varying degrees, prevent viral replication via interactions with the largely conserved active site pockets. KEYWORDS: Severe Acute Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus; Severe Acute Respiratory Syndrome Coronavirus 2; Replicase Polypeptide; Protease; Neuraminidase Inhibitor; Peptidomimetic Inhibitor; α-Ketoamide Inhibitor; Molecular Docking

scholarly journals Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro

2021 ◽  
Vol 57 (78) ◽  
pp. 10083-10086
Author(s):  
Love Panchariya ◽  
Wajahat Ali Khan ◽  
Shobhan Kuila ◽  
Kirtishila Sonkar ◽  
Sibasis Sahoo ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Viral Replication ◽  
Active Site ◽  
Main Protease

Zn2+ binds to the active site of the SARS-CoV-2 main protease (Mpro), and inhibits enzyme activity and viral replication in vitro.

scholarly journals In Silico Screening of Naturally Occurring Coumarin Derivatives for the Inhibition of the Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Sona Lyndem ◽  
Sharat Sarmah ◽  
Sourav Das ◽  
Atanu Singha Roy
Keyword(s):  
Active Site ◽  
Preliminary Screening ◽  
Naturally Occurring ◽  
Main Protease ◽  
Coumarin Compounds ◽  
Potential Inhibitors ◽  
Novel Drug ◽  
Catalytic Dyad

<p>The dissemination of a novel corona virus, SARS-CoV-2, through rapid human to human transmission has led to a global health emergency. The lack of a vaccine or medication for effective treatment of this disease has made it imperative for developing novel drug discovery approaches. Repurposing of drugs is one such method currently being used to tackle the viral infection. The genome of SARS-CoV-2 replicates due to the functioning of a main protease called M<sup>pro</sup>. By targeting the active site of M<sup>pro</sup> with potential inhibitors, this could prevent viral replication from taking place. Blind docking technique was used to investigate the interactions between 29 naturally occurring coumarin compounds and SARS-CoV-2 main protease, M<sup>pro</sup>, out of which 17 coumarin compounds were seen to bind to the active site through the interaction with the catalytic dyad, His41 and Cys145, along with other neighbouring residues. On comparing the ΔG values of the coumarins bound to the active site of M<sup>pro</sup>, corymbocoumarin belonging to the class pyranocoumarins, methylgalbanate belonging to the class simple coumarins and heraclenol belonging to the class furanocoumarins, displayed best binding efficiency and could be considered as potential M<sup>pro</sup> protease inhibitors. Preliminary screening of these naturally occurring coumarin compounds as potential SARS-CoV-2 replication inhibitors acts as a stepping stone for further <i>in vitro</i> and <i>in vivo</i> experimental investigation and analytical validation. </p>

scholarly journals In Silico Screening of Naturally Occurring Coumarin Derivatives for the Inhibition of the Main Protease of SARS-CoV-2

2020 ◽  
Author(s):  
Sona Lyndem ◽  
Sharat Sarmah ◽  
Sourav Das ◽  
Atanu Singha Roy
Keyword(s):  
Active Site ◽  
Preliminary Screening ◽  
Naturally Occurring ◽  
Main Protease ◽  
Coumarin Compounds ◽  
Potential Inhibitors ◽  
Novel Drug ◽  
Catalytic Dyad

<p>The dissemination of a novel corona virus, SARS-CoV-2, through rapid human to human transmission has led to a global health emergency. The lack of a vaccine or medication for effective treatment of this disease has made it imperative for developing novel drug discovery approaches. Repurposing of drugs is one such method currently being used to tackle the viral infection. The genome of SARS-CoV-2 replicates due to the functioning of a main protease called M<sup>pro</sup>. By targeting the active site of M<sup>pro</sup> with potential inhibitors, this could prevent viral replication from taking place. Blind docking technique was used to investigate the interactions between 29 naturally occurring coumarin compounds and SARS-CoV-2 main protease, M<sup>pro</sup>, out of which 17 coumarin compounds were seen to bind to the active site through the interaction with the catalytic dyad, His41 and Cys145, along with other neighbouring residues. On comparing the ΔG values of the coumarins bound to the active site of M<sup>pro</sup>, corymbocoumarin belonging to the class pyranocoumarins, methylgalbanate belonging to the class simple coumarins and heraclenol belonging to the class furanocoumarins, displayed best binding efficiency and could be considered as potential M<sup>pro</sup> protease inhibitors. Preliminary screening of these naturally occurring coumarin compounds as potential SARS-CoV-2 replication inhibitors acts as a stepping stone for further <i>in vitro</i> and <i>in vivo</i> experimental investigation and analytical validation. </p>

scholarly journals Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

2021 ◽  
Vol 22 (6) ◽  
pp. 3163
Author(s):  
Hirofumi Ohashi ◽  
Feng Wang ◽  
Frank Stappenbeck ◽  
Kana Tsuchimoto ◽  
Chisa Kobayashi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Cultured Cells ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Membrane Vesicles ◽  
Drug Candidates ◽  
Increased Risk ◽  
Derivatives Of

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.

scholarly journals First-in-Woman Safety, Tolerability, and Pharmacokinetics of Orally Administered GS-441524: A Broad-Spectrum Antiviral Treatment for COVID-19

2021 ◽  
Author(s):  
Victoria Yan
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Broad Spectrum ◽  
Half Life ◽  
Maximum Concentration ◽  
Viral Infections ◽  
Clinical Laboratory ◽  
Antiviral Treatment ◽  
Oral Solution ◽  
Healthy Human

GS-441524 is a nucleoside analogue with broad-spectrum antiviral activity against RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and feline coronavirus (FCoV). GS-441524 is the main circulating metabolite following intravenous administration of remdesivir (Veklury®), with a plasma half-life of approximately 24 hours. The safety, tolerability, and pharmacokinetics of GS-441524 was evaluated in a healthy human volunteer (N=1) when administered directly as an oral solution (750 mg) once daily for 7 days (Part 1) and 3 times daily for 3 days (Part 2). In Part 1 of the study, the effect of food on the absorption of GS-441524 was also evaluated. GS-441524 appeared rapidly in plasma, with an average time of maximum concentration of 0.5 hours during once-per-day dosing and exhibited an initial half-life phase of approximately 3.3 hours in the fasted state. Negligible accumulation was observed during part 1 of the multiday study. In Part 2 of the study, GS-441524 was administered 3 times daily, every 3 hours. A 2-4-fold accumulation of GS-441524 was observed approximately 3 hours after the third dose was administered, with a time of maximum concentration of 9 hours and a maximum concentration of 12.01 µM, exceeding the concentration reported to eradicate SARS-CoV-2 in vitro. For the duration of the study, GS-441524 was well-tolerated. There were no treatment-related adverse events and no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Taken together, these results demonstrate the safety and viability of orally administered GS-441524 for the treatment of COVID-19 and emerging viral infections.

scholarly journals A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

2020 ◽  
Vol 7 ◽  
Author(s):  
Rounak Chourasia ◽  
Srichandan Padhi ◽  
Loreni Chiring Phukon ◽  
Md Minhajul Abedin ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Drug Targets ◽  
Docking Studies ◽  
Lactobacillus Delbrueckii ◽  
Amino Acid Residues ◽  
Main Protease ◽  
Effective Inhibition ◽  
Cheese Peptides ◽  
Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

scholarly journals Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021 ◽  
Vol 9 ◽  
Author(s):  
Hylemariam Mihiretie Mengist ◽  
Tebelay Dilnessa ◽  
Tengchuan Jin
Keyword(s):  
Life Cycle ◽  
Patient Management ◽  
Social Economic ◽  
Structural Basis ◽  
Supportive Treatment ◽  
Future Directions ◽  
Main Protease ◽  
The World ◽  
Repurposed Drugs ◽  
Potential Inhibitors

The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

scholarly journals Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Carlos Javier Alméciga-Díaz ◽  
Luisa N. Pimentel-Vera ◽  
Angela Caro ◽  
Angela Mosquera ◽  
Camilo Andrés Castellanos Moreno ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Clinical Information ◽  
Virus Genome ◽  
Pharmacological Agents ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

scholarly journals COMPUTATIONAL SCREENING AND MOLECULAR DOCKING OF LICHEN SECONDARY METABOLITES AGAINST SEVERE ACUTE RESPIRATORY SYNDROME-COV-2 MAIN PROTEASE AND SPIKE PROTEIN

2021 ◽  
pp. 100-104
Author(s):  
SENTHIL PRABHU S ◽  
SATHISHKUMAR R ◽  
KIRUTHIKA B
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
Study Finding ◽  
Spike Protein ◽  
Protein Targets ◽  
Lipinski’S Rule ◽  
Computational Screening ◽  
Main Protease ◽  
Lichen Compounds ◽  
Potential Inhibitors

Objective: At present, the coronavirus disease (COVID)-19 pandemic is increasing global health concerns. This coronavirus outbreak is caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Since, no specific antiviral for treatment against COVID-19, so identification of new therapeutics is an urgent need. The objective of this study is to the analysis of lichen compounds against main protease and spike protein targets of SARS-CoV-2 using in silico approach. Methods: A total of 108 lichen compounds were subjected to ADMET analysis and 14 compounds were selected based on the ADMET properties and Lipinski’s rule of five. Molecular docking was performed for screening of selected individual lichen metabolites against the main protease and spike proteins of SARS-CoV-2 by Schrodinger Glide module software. Results: Among the lead compounds, fallacinol showed the highest binding energy value of −11.83 kcal/mol against spike protein, 4-O-Demethylbarbatic acid exhibited the highest dock score of −11.67 kcal/mol against main protease. Conclusion: This study finding suggests that lichen substances may be potential inhibitors of SARS-CoV-2.

scholarly journals In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

2020 ◽  
Author(s):  
Yogesh Kumar ◽  
Harvijay Singh
Keyword(s):  
Virtual Screening ◽  
Active Site ◽  
Viral Infections ◽  
Drug Repurposing ◽  
Docking Study ◽  
Docking Studies ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

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