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1.
Nat Commun ; 11(1): 4252, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741685

ABSTRACT

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Influenza A virus/drug effects , Peptides/pharmacology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Cell Line , Endosomes/chemistry , Endosomes/drug effects , Female , Humans , Hydrogen-Ion Concentration , Influenza A virus/metabolism , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/metabolism , Peptides/chemistry , Peptides/metabolism , Peptides/therapeutic use , Protein Binding , Protein Conformation , Rhinovirus/drug effects , Rhinovirus/metabolism , Viral Load/drug effects , Virus Replication/drug effects
2.
SAR QSAR Environ Res ; 31(9): 643-654, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-733459

ABSTRACT

A quantitative structure-activity relationship (QSAR) model was built from a dataset of 54 peptide-type compounds as SARS-CoV inhibitors. The analysis was executed to identify prominent and hidden structural features that govern anti-SARS-CoV activity. The QSAR model was derived from the genetic algorithm-multi-linear regression (GA-MLR) methodology. This resulted in the generation of a statistically robust and highly predictive model. In addition, it satisfied the OECD principles for QSAR validation. The model was validated thoroughly and fulfilled the threshold values of a battery of statistical parameters (e.g. r 2 = 0.87, Q 2 loo = 0.82). The derived model is successful in identifying many atom-pairs as important structural features that govern the anti-SARS-CoV activity of peptide-type compounds. The newly developed model has a good balance of descriptive and statistical approaches. Consequently, the present work is useful for future modifications of peptide-type compounds for SARS-CoV and SARS-CoV-2 activity.


Subject(s)
Antiviral Agents , Betacoronavirus/drug effects , Peptides , Quantitative Structure-Activity Relationship , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/enzymology , Cysteine Endopeptidases , Inhibitory Concentration 50 , Linear Models , Molecular Structure , Peptides/chemistry , Peptides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors
3.
F1000Res ; 9: 576, 2020.
Article in English | MEDLINE | ID: covidwho-721640

ABSTRACT

Background: There are no known medicines or vaccines to control the COVID-19 pandemic caused by SARS-CoV-2 (nCoV). Antiviral peptides are superior to conventional drugs and may also be effective against COVID-19. Hence, we investigated the SARS-CoV-2 Spike receptor-binding domain (nCoV-RBD) that interacts with hACE2 for viral attachment and entry. Methods: Three strategies and bioinformatics approaches were employed to design potential nCoV-RBD - hACE2 interaction-blocking peptides that may restrict viral attachment and entry. Firstly, the key residues interacting with nCoV-RBD - hACE2 are identified and hACE2 sequence-based peptides are designed. Second, peptides from five antibacterial peptide databases that block nCoV-RBD are identified; finally, a chimeric peptide design approach is used to design peptides that can bind to key nCoV-RBD residues. The final peptides are selected based on their physiochemical properties, numbers and positions of key residues binding, binding energy, and antiviral properties. Results: We found that: (i) three amino acid stretches in hACE2 interact with nCoV-RBD; (ii) effective peptides must bind to three key positions of nCoV-RBD (Gly485/Phe486/Asn487, Gln493, and Gln498/Thr500/Asn501); (iii) Phe486, Gln493, and Asn501 are critical residues; (iv) AC20 and AC23 derived from hACE2 may block two key critical positions; (iv) DBP6 identified from databases can block the three sites of the nCoV-RBD and interacts with one critical position, Gln498; (v) seven chimeric peptides were considered promising, among which cnCoVP-3, cnCoVP-4, and cnCoVP-7 are the top three; and (vi) cnCoVP-4 meets all the criteria and is the best peptide. Conclusions: To conclude, using three different bioinformatics approaches, we identified 17 peptides that can potentially bind to the nCoV-RBD that interacts with hACE2. Binding these peptides to nCoV-RBD may potentially inhibit the virus to access hACE2 and thereby may prevent the infection. Out of 17, 10 peptides have promising potential and need further experimental validation.


Subject(s)
Coronavirus Infections , Pandemics , Peptides/pharmacology , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Betacoronavirus , Humans , Receptors, Virus/chemistry
4.
Int J Mol Sci ; 21(15)2020 Jul 23.
Article in English | MEDLINE | ID: covidwho-669635

ABSTRACT

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Clinical Trials as Topic , Humans , Pandemics , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Polysaccharides/chemistry , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Virus Attachment/drug effects , Virus Internalization/drug effects
5.
Drugs R D ; 20(3): 161-169, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-615258

ABSTRACT

BACKGROUND AND OBJECTIVE: Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. METHODS: Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. RESULTS: We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. CONCLUSION: Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Peptides/pharmacology , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/isolation & purification , Coronavirus Infections/virology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Viral Vaccines/pharmacology
6.
Aging (Albany NY) ; 12(12): 11263-11276, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-601536

ABSTRACT

The outbreak of COVID-19 has now become a global pandemic that has severely impacted lives and economic stability. There is, however, no effective antiviral drug that can be used to treat COVID-19 to date. Built on the fact that SARS-CoV-2 initiates its entry into human cells by the receptor binding domain (RBD) of its spike protein binding to the angiotensin-converting enzyme 2 (hACE2), we extended a recently developed approach, EvoDesign, to design multiple peptide sequences that can competitively bind to the SARS-CoV-2 RBD to inhibit the virus from entering human cells. The protocol starts with the construction of a hybrid peptidic scaffold by linking two fragments grafted from the interface of the hACE2 protein (a.a. 22-44 and 351-357) with a linker glycine, which is followed by the redesign and refinement simulations of the peptide sequence to optimize its binding affinity to the interface of the SARS-CoV-2 RBD. The binding experiment analyses showed that the designed peptides exhibited a significantly stronger binding potency to hACE2 than the wild-type hACE2 receptor (with -53.35 vs. -46.46 EvoEF2 energy unit scores for the top designed and wild-type peptides, respectively). This study demonstrates a new avenue to utilize computationally designed peptide motifs to treat the COVID-19 disease by blocking the critical spike-RBD and hACE2 interactions.


Subject(s)
Coronavirus Infections/drug therapy , Peptides/chemical synthesis , Peptides/pharmacology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/physiology , Amino Acid Sequence , Antiviral Agents , Binding Sites , Drug Design , Evolution, Molecular , Humans , Models, Molecular , Pandemics , Protein Binding , Protein Conformation , Virus Internalization/drug effects
7.
ACS Comb Sci ; 22(6): 297-305, 2020 06 08.
Article in English | MEDLINE | ID: covidwho-247796

ABSTRACT

A new coronavirus (CoV) caused a pandemic named COVID-19, which has become a global health care emergency in the present time. The virus is referred to as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) and has a genome similar (∼82%) to that of the previously known SARS-CoV (SARS coronavirus). An attractive therapeutic target for CoVs is the main protease (Mpro) or 3-chymotrypsin-like cysteine protease (3CLpro), as this enzyme plays a key role in polyprotein processing and is active in a dimeric form. Further, Mpro is highly conserved among various CoVs, and a mutation in Mpro is often lethal to the virus. Thus, drugs targeting the Mpro enzyme significantly reduce the risk of mutation-mediated drug resistance and display broad-spectrum antiviral activity. The combinatorial design of peptide-based inhibitors targeting the dimerization of SARS-CoV Mpro represents a potential therapeutic strategy. In this regard, we have compiled the literature reports highlighting the effect of mutations and N-terminal deletion of residues of SARS-CoV Mpro on its dimerization and, thus, catalytic activity. We believe that the present review will stimulate research in this less explored yet quite significant area. The effect of the COVID-19 epidemic and the possibility of future CoV outbreaks strongly emphasize the urgent need for the design and development of potent antiviral agents against CoV infections.


Subject(s)
Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/metabolism , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Multimerization/drug effects , Viral Nonstructural Proteins/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Betacoronavirus/genetics , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Drug Discovery , Humans , Models, Molecular , Molecular Targeted Therapy , Mutation/drug effects , Pandemics , Peptides/pharmacology , Pneumonia, Viral/virology , Protein Conformation/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
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