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1.
Drug Des Devel Ther ; 16: 1067-1082, 2022.
Article in English | MEDLINE | ID: covidwho-1808738

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a threat to human health. 3C-like proteinase (3CLpro) plays an important role in the viral life cycle. Hence, it is considered an attractive antiviral target protein. Whole-genome sequencing showed that the sequence homology between SARS-CoV-2 3CLpro and SARS-CoV 3CLpro is 96.08%, with high similarity in the substrate-binding region. Thus, assessing peptidomimetic inhibitors of SARS-CoV 3CLpro could accelerate the development of peptidomimetic inhibitors for SARS-CoV-2 3CLpro. Accordingly, we herein discuss progress on SARS-CoV-2 3CLpro peptidomimetic inhibitors. Inflammation plays a major role in the pathophysiological process of COVID-19. Small-molecule compounds targeting 3CLpro with both antiviral and anti-inflammatory effects are also briefly discussed in this paper.


Subject(s)
COVID-19 , Peptidomimetics , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases , Humans , Peptide Hydrolases , Peptidomimetics/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
2.
Int J Mol Sci ; 23(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1715403

ABSTRACT

As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CLPro), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CLPro-specific drug candidates were determined by the interplay between 3CLPro H41 residue and the peptidomimetic inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Peptidomimetics/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Drug Design , Fluorescence Resonance Energy Transfer , Histidine/chemistry , Ligands , Molecular Dynamics Simulation , Peptidomimetics/chemistry , Protease Inhibitors/chemistry , Structure-Activity Relationship , Vero Cells
3.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1705973

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
4.
Chem Commun (Camb) ; 58(11): 1804-1807, 2022 Feb 03.
Article in English | MEDLINE | ID: covidwho-1639537

ABSTRACT

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 µM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Peptide Fragments/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
5.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1340972

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
6.
Bioorg Med Chem ; 46: 116301, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1333256

ABSTRACT

Severe Acute Respiratory Syndrome (SARS) is a severe febrile respiratory disease caused by the beta genus of human coronavirus, known as SARS-CoV. Last year, 2019-n-CoV (COVID-19) was a global threat for everyone caused by the outbreak of SARS-CoV-2. 3CLpro, chymotrypsin-like protease, is a major cysteine protease that substantially contributes throughout the viral life cycle of SARS-CoV and SARS-CoV-2. It is a prospective target for the development of SARS-CoV inhibitors by applying a repurposing strategy. This review focuses on a detailed overview of the chemical synthesis and computational chemistry perspectives of peptidomimetic inhibitors (PIs) and small-molecule inhibitors (SMIs) targeting viral proteinase discovered from 2004 to 2020. The PIs and SMIs are one of the primary therapeutic inventions for SARS-CoV. The journey of different analogues towards the evolution of SARS-CoV 3CLpro inhibitors and complete synthetic preparation of nineteen derivatives of PIs and ten derivatives of SMIs and their computational chemistry perspectives were reviewed. From each class of derivatives, we have identified and highlighted the most compelling PIs and SMIs for SARS-CoV 3CLpro. The protein-ligand interaction of 29 inhibitors were also studied that involved with the 3CLpro inhibition, and the frequent amino acid residues of the protease were also analyzed that are responsible for the interactions with the inhibitors. This work will provide an initiative to encourage further research for the development of effective and drug-like 3CLpro inhibitors against coronaviruses in the near future.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS Virus/drug effects , Animals , Antiviral Agents/chemical synthesis , Cell Line, Tumor , Cysteine Proteinase Inhibitors/chemical synthesis , Humans , Peptidomimetics/chemical synthesis , SARS Virus/enzymology , SARS-CoV-2/enzymology
7.
J Med Chem ; 65(4): 2926-2939, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1327181

ABSTRACT

The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Ketones/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Humans , Ketones/chemistry , Male , Microbial Sensitivity Tests , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Rats , Rats, Wistar , SARS-CoV-2/enzymology , Vero Cells
8.
J Med Chem ; 65(4): 2905-2925, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1303733

ABSTRACT

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Virus Replication/drug effects
9.
Biomolecules ; 11(4)2021 04 19.
Article in English | MEDLINE | ID: covidwho-1194605

ABSTRACT

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020-2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO's main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (Mpro) are becoming more and more promising candidates. Mpro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 Mpro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 Mpro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Peptidomimetics/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/chemistry , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Drug Repositioning , Humans , Molecular Docking Simulation , Peptidomimetics/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Small Molecule Libraries/chemistry
10.
J Med Chem ; 65(4): 2794-2808, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1192017

ABSTRACT

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 µM, EC50 = 0.29 µM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.


Subject(s)
Aldehydes/pharmacology , Antiviral Agents/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Enterovirus/drug effects , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Aldehydes/chemical synthesis , Aldehydes/chemistry , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Structure-Activity Relationship
11.
Viruses ; 13(2)2021 02 09.
Article in English | MEDLINE | ID: covidwho-1128060

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than two million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin-a de novo designed synthetic small molecule that captures the biological properties of HDPs-on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is likely to be a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 against different strains of the virus in cell culture.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Guanidines/pharmacology , Pyrimidines/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/virology , Cell Culture Techniques , Cell Line , Chlorocebus aethiops , Defensins/pharmacology , Humans , Peptidomimetics/pharmacology , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
12.
Bioorg Med Chem Lett ; 30(17): 127377, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-627941

ABSTRACT

The unprecedented pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening global health. The virus emerged in late 2019 and can cause a severe disease associated with significant mortality. Several vaccine development and drug discovery campaigns are underway. The SARS-CoV-2 main protease is considered a promising drug target, as it is dissimilar to human proteases. Sequence and structure of the main protease are closely related to those from other betacoronaviruses, facilitating drug discovery attempts based on previous lead compounds. Covalently binding peptidomimetics and small molecules are investigated. Various compounds show antiviral activity in infected human cells.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amino Acid Sequence , Animals , Antiviral Agents/pharmacokinetics , Betacoronavirus/enzymology , Cell Line , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Discovery , Humans , Peptidomimetics/pharmacokinetics , Peptidomimetics/pharmacology , SARS-CoV-2 , Substrate Specificity , Viral Nonstructural Proteins/chemistry
13.
J Med Chem ; 63(9): 4562-4578, 2020 05 14.
Article in English | MEDLINE | ID: covidwho-613484

ABSTRACT

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Enterovirus/drug effects , Lactams/pharmacology , Peptidomimetics/pharmacology , Virus Replication/drug effects , 3C Viral Proteases , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus/enzymology , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Design , Enterovirus/enzymology , Humans , Lactams/chemical synthesis , Lactams/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protein Binding , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Proteins/metabolism
14.
Comput Biol Med ; 121: 103749, 2020 06.
Article in English | MEDLINE | ID: covidwho-46680

ABSTRACT

This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2' spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles' heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried out suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding sites. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Viral Vaccines/immunology , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/genetics , Betacoronavirus/immunology , Binding Sites , COVID-19 , COVID-19 Vaccines , Computational Biology , Coronavirus/chemistry , Coronavirus/genetics , Coronavirus/immunology , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/virology , Drug Design , Drug Resistance, Viral/genetics , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Models, Molecular , Mutation , Peptidomimetics/pharmacology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Viral Vaccines/genetics
15.
Comput Biol Med ; 119: 103670, 2020 04.
Article in English | MEDLINE | ID: covidwho-1938

ABSTRACT

This paper concerns study of the genome of the Wuhan Seafood Market isolate believed to represent the causative agent of the disease COVID-19. This is to find a short section or sections of viral protein sequence suitable for preliminary design proposal for a peptide synthetic vaccine and a peptidomimetic therapeutic, and to explore some design possibilities. The project was originally directed towards a use case for the Q-UEL language and its implementation in a knowledge management and automated inference system for medicine called the BioIngine, but focus here remains mostly on the virus itself. However, using Q-UEL systems to access relevant and emerging literature, and to interact with standard publically available bioinformatics tools on the Internet, did help quickly identify sequences of amino acids that are well conserved across many coronaviruses including 2019-nCoV. KRSFIEDLLFNKV was found to be particularly well conserved in this study and corresponds to the region around one of the known cleavage sites of the SARS virus that are believed to be required for virus activation for cell entry. This sequence motif and surrounding variations formed the basis for proposing a specific synthetic vaccine epitope and peptidomimetic agent. The work can, nonetheless, be described in traditional bioinformatics terms, and readily reproduced by others, albeit with the caveat that new data and research into 2019-nCoV is emerging and evolving at an explosive pace. Preliminary studies using molecular modeling and docking, and in that context the potential value of certain known herbal extracts, are also described.


Subject(s)
Betacoronavirus/immunology , Betacoronavirus/physiology , Computational Biology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Peptidomimetics/chemistry , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Viral Vaccines , Amino Acid Sequence , Animals , Betacoronavirus/chemistry , Betacoronavirus/drug effects , COVID-19 , COVID-19 Vaccines , Computer Simulation , Coronavirus/chemistry , Coronavirus Infections/drug therapy , Drug Design , Epitopes , Genome, Viral , Humans , Models, Molecular , Peptidomimetics/metabolism , Peptidomimetics/pharmacology , Pneumonia, Viral/drug therapy , Programming Languages , Protein Conformation , Protein Structure, Secondary , SARS-CoV-2 , Sequence Homology, Amino Acid , Software , Spike Glycoprotein, Coronavirus/chemistry , Vaccines, Synthetic , Viral Vaccines/chemistry , Virus Internalization
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