scholarly journals Omicron: A heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escape approved COVID-19 therapeutic antibodies

2021 ◽  
Author(s):  
Masaud Shah ◽  
Hyun Goo Woo
Keyword(s):  
South Africa ◽  
Electrostatic Potential ◽  
Binding Energies ◽  
Phase Iii ◽  
Therapeutic Antibodies ◽  
Free Energies ◽  
Significant Drop ◽  
Phase Iii Clinical Trials ◽  
Computational Mutagenesis ◽  
Binding Free Energies

AbstractThe new SARS-CoV-2 variant of concern “Omicron” was recently (Nov. 24th. 2021) spotted in South Africa and already spread around the world due to its enhanced transmissibility. The variant became conspicuous as it harbors more than thirty mutations in the spike protein with 15 mutations in the RBD region alone, potentially dampening the potency of therapeutic antibodies and enhancing the ACE2 binding. More worrying, Omicron infections have been reported in individuals who have received vaccines jabs in South Africa and Hong Kong. Here, we investigated the binding strength of Omicron with ACE2 and seven monoclonal antibodies that are either approved by FDA for COVID-19 therapy or undergoing phase III clinical trials. Computational mutagenesis and binding free energies could confirm that Omicron Spike binds ACE2 stronger than prototype SARS-CoV-2. Notably, three substitutions, i.e., T478K, Q493K, and Q498R, significantly contribute to the binding energies and doubled electrostatic potential of the RBDOmic-ACE2 complex. Instead of E484K substitution that helped neutralization escape of Beta, Gamma, and Mu variants, Omicron harbors E484A substitution. Together, T478K, Q493K, Q498R, and E484A substitutions contribute to a significant drop in the electrostatic potential energies between RBDOmic-mAbs, particularly in Etesevimab, Bamlanivimab, and CT-p59. CDR diversification could help regain the neutralization strength of these antibodies; however, we could not conduct this analysis to this end. Conclusively, our findings suggest that Omicron binds ACE2 with greater affinity, enhancing its infectivity and transmissibility. Mutations in the Spike are prudently devised by the virus that enhances the receptor binding and weakens the mAbs binding to escape the immune response.

scholarly journals A simple model for predicting the free energy of binding between anthracycline antibiotics and DNA.

2000 ◽  
Vol 47 (1) ◽  
pp. 1-9 ◽  
Author(s):  
W R Rudnicki ◽  
M Kurzepa ◽  
T Szczepanik ◽  
W Priebe ◽  
B Lesyng
Keyword(s):  
Free Energy ◽  
Theoretical Model ◽  
Density Functional ◽  
Binding Free Energy ◽  
Binding Energies ◽  
Free Energies ◽  
Anthracycline Antibiotics ◽  
Free Energy Of Binding ◽  
Derivatives Of ◽  
Binding Free Energies

A theoretical model for predicting the free energy of binding between anthracycline antibiotics and DNA was developed using the electron density functional (DFT) and molecular mechanics (MM) methods. Partial DFT-ESP charges were used in calculating the MM binding energies for complexes formed between anthracycline antibiotics and oligodeoxynucleotides. These energies were then compared with experimental binding free energies. The good correlation between the experimental and theoretical energies allowed us to propose a model for predicting the binding free energy for derivatives of anthracycline antibiotics and for quickly screening new anthracycline derivatives.

Identifying MurI uncompetitive inhibitors by correlating decomposed binding energies with bioactivity

RSC Advances ◽  
2015 ◽  
Vol 5 (51) ◽  
pp. 40536-40545 ◽  
Author(s):  
Xiu Le ◽  
Qiong Gu ◽  
Jun Xu
Keyword(s):  
Binding Energies ◽  
New Method ◽  
Free Energies ◽  
Binding Free Energies

MurI uncompetitive inhibitors can be virtually identified by a new method that correlates decomposed binding free energies with the bioactivity.

Repurposing Known Drugs as Covalent and Non-Covalent Inhibitors of the SARS-CoV-2 Papain-like Protease

2020 ◽  
Author(s):  
Pietro Delre ◽  
Fabiana Caporuscio ◽  
Michele Saviano ◽  
Giuseppe Felice Mangiatordi
Keyword(s):  
Phase Iii ◽  
Free Energies ◽  
Ligand Interaction ◽  
Health Crisis ◽  
Covalent Inhibitors ◽  
Traditional Drug ◽  
Drug Discovery Program ◽  
Protein Ligand Interaction ◽  
Binding Free Energies

<p>In the absence of an approved vaccine, developing effective SARS-CoV-2 antivirals is essential to tackle the current pandemic health crisis due to the COVID-19 spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, <i>in silico</i> repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. Herein we present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multi-target activities for the COVID-19 treatment. A dataset including 688 phase III and 1702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein-ligand interaction fingerprint similarities, conventional docking scores and MMGBSA binding free energies and allowed the identification of some interesting candidates for further <i>in-vitro</i> testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.<b></b></p>

Repurposing Known Drugs as Covalent and Non-Covalent Inhibitors of the SARS-CoV-2 Papain-like Protease

2020 ◽  
Author(s):  
Pietro Delre ◽  
Fabiana Caporuscio ◽  
Michele Saviano ◽  
Giuseppe Felice Mangiatordi
Keyword(s):  
Phase Iii ◽  
Free Energies ◽  
Ligand Interaction ◽  
Health Crisis ◽  
Covalent Inhibitors ◽  
Traditional Drug ◽  
Drug Discovery Program ◽  
Protein Ligand Interaction ◽  
Binding Free Energies

<p>In the absence of an approved vaccine, developing effective SARS-CoV-2 antivirals is essential to tackle the current pandemic health crisis due to the COVID-19 spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, <i>in silico</i> repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. Herein we present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multi-target activities for the COVID-19 treatment. A dataset including 688 phase III and 1702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein-ligand interaction fingerprint similarities, conventional docking scores and MMGBSA binding free energies and allowed the identification of some interesting candidates for further <i>in-vitro</i> testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.<b></b></p>

scholarly journals Therapeutic Aptamers: Evolving to Find their Clinical Niche

2020 ◽  
Vol 27 (25) ◽  
pp. 4181-4193 ◽  
Author(s):  
Shahid M. Nimjee ◽  
Bruce A. Sullenger
Keyword(s):  
Clinical Trials ◽  
Nucleic Acid ◽  
Combinatorial Chemistry ◽  
Clinical Studies ◽  
Three Dimensional ◽  
Therapeutic Targets ◽  
Phase Iii ◽  
Therapeutic Antibodies ◽  
Target Validation ◽  
Phase Iii Clinical Trials

Background: The discovery that short oligonucleotides, termed aptamers, can fold into three-dimensional structures that allow them to selectively bind and inhibit the activity of pathogenic proteins is now over 25 years old. The invention of the SELEX methodology heralded in an era in which such nucleic acid-based ligands could be generated against a wide variety of therapeutic targets. Results: A large number of aptamers have now been identified by combinatorial chemistry methods in the laboratory and moreover, an increasing number have been discovered in nature. The affinities and activities of such aptamers have often been compared to that of antibodies, yet only a few of these agents have made it into clinical studies compared to a large and increasing number of therapeutic antibodies. One therapeutic aptamer targeting VEGF has made it to market, while 3 others have advanced as far as phase III clinical trials. Conclusion: In this manuscript, we hope the reader appreciates that the success of aptamers becoming a class of drugs is less about nucleic acid biochemistry and more about target validation and overall drug chemistry.

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

2001 ◽  
Vol 120 (5) ◽  
pp. A284-A284
Author(s):  
B NAULT ◽  
S SUE ◽  
J HEGGLAND ◽  
S GOHARI ◽  
G LIGOZIO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Irritable Bowel Syndrome ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Irritable Bowel ◽  
Rome I

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials

2001 ◽  
Vol 28 (6) ◽  
pp. 620-625 ◽  
Author(s):  
Pierre Falardeau ◽  
Pierre Champagne ◽  
Patrick Poyet ◽  
Claude Hariton ◽  
[Eacute]ric Dupont
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Naturally Occurring ◽  
Antiangiogenic Drug

scholarly journals Animal and Human Vaccines against West Nile Virus

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1073
Author(s):  
Juan-Carlos Saiz
Keyword(s):  
Clinical Trials ◽  
West Nile Virus ◽  
Vaccine Development ◽  
Phase Iii ◽  
West Nile ◽  
Specific Therapy ◽  
Phase Iii Clinical Trials ◽  
Neuroinvasive Disease ◽  
The Us ◽  
The Status

West Nile virus (WNV) is a widely distributed enveloped flavivirus transmitted by mosquitoes, which main hosts are birds. The virus sporadically infects equids and humans with serious economic and health consequences, as infected individuals can develop a severe neuroinvasive disease that can even lead to death. Nowadays, no WNV-specific therapy is available and vaccines are only licensed for use in horses but not for humans. While several methodologies for WNV vaccine development have been successfully applied and have contributed to significantly reducing its incidence in horses in the US, none have progressed to phase III clinical trials in humans. This review addresses the status of WNV vaccines for horses, birds, and humans, summarizing and discussing the challenges they face for their clinical advance and their introduction to the market.

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