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1.
Molecules ; 27(7)2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1785839

ABSTRACT

Respiratory syncytial virus infection (RSVI) is an acute medical and social problem in many countries globally. Infection is most dangerous for infants under one year old and the elderly. Despite its epidemiological relevance, only two drugs are registered for clinical use against RSVI: ribavirin (approved in a limited number of countries due to side effects) and palivizumab (Synagis), which is intended only for the prevention, but not the treatment, of infection. Currently, various research groups are searching for new drugs against RSV, with three main areas of research: small molecules, polymeric drugs (proteins and peptides), and plant extracts. This review is devoted to currently developed protein and peptide anti-RSV drugs.


Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Tract Infections , Aged , Antiviral Agents/therapeutic use , Humans , Infant , Palivizumab/therapeutic use , Peptides/pharmacology , Peptides/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Tract Infections/drug therapy
2.
Molecules ; 27(7)2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1785838

ABSTRACT

Obesity is the most common nutritional disorder in the developed world and is associated with important comorbidities. Pancreatic lipase (PL) inhibitors play a key role in the metabolism of human fat. A series of novel epoxyketones peptide derivatives were investigated for their pancreatic lipase inhibitory activity. The epoxyketone moiety is a well-known reactive electrophile group that has been used as part of proteasome inhibitors in cancer therapy, and it is widely believed that these are very selective for targeting the proteasome active site. Here we investigated various peptide derivatives with an epoxide warhead for their anti-lipase activity. The assessment of these novel epoxyketones was performed by an in-house method that we developed for rapid screening and identification of lipase inhibitors using GC-FID. Herein, we present a novel anti-lipase pharmacophore based on epoxyketone peptide derivatives that showed potent anti-lipase activity. Many of these derivatives had comparable or more potent activity than the clinically used lipase inhibitors such as orlistat. In addition, the lipase appears to be inhibited by a wide range of epoxyketone analogues regardless of the configuration of the epoxide in the epoxyketone moiety. The presented data in this study shows the first example of the use of epoxyketone peptides as novel lipase inhibitors.


Subject(s)
Peptides , Proteasome Inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Epoxy Compounds/pharmacology , Humans , Lipase , Peptides/chemistry , Peptides/pharmacology , Proteasome Endopeptidase Complex/chemistry , Proteasome Inhibitors/chemistry
3.
Adv Exp Med Biol ; 1366: 87-100, 2022.
Article in English | MEDLINE | ID: covidwho-1782742

ABSTRACT

The continued HIV/AIDS epidemic worldwide and the battle against emerging infectious diseases caused by coronaviruses underscore the need for the development of an ever-expanding repertoire of antiviral drugs. Entry inhibitors are of particular interest because of their potential to be used as therapeutic or prophylactic treatments for blocking viral invasion. HIV and coronaviruses utilize class I fusion proteins to facilitate their entry and membrane fusion. Discovery of a common hexameric coiled-coil fusion complex resulting from the packing of three C-terminal heptad repeat region from the fusion-mediating subunit of viral fusion proteins against trimeric coiled-coil made up by their N-terminal heptad repeat prompted the search for peptides mimicking the heptad repeat regions that could potentially inhibit viral entry. This has led to the development of effective peptides that are specific to the virus that is developed for. In this review, we focus on peptide-based entry dual inhibitors that block fusion process not only of HIV but also coronaviruses through interrupting their fusogenic six-helical bundle core and which hopefully will help to gain insight into the α-helical secondary structure- and coiled-coil superstructure-based strategies to design entry inhibitors with broad-spectrum antiviral activity against enveloped viruses with class I fusion proteins.


Subject(s)
Coronavirus Infections , Coronavirus , HIV Infections , Amino Acid Sequence , Antiviral Agents/pharmacology , HIV Envelope Protein gp41/metabolism , HIV Envelope Protein gp41/pharmacology , Humans , Peptides/pharmacology , Protein Structure, Secondary
4.
Bioengineered ; 13(4): 9435-9454, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1778851

ABSTRACT

Betacoronaviruses (ß-CoVs) have caused major viral outbreaks in the last two decades in the world. The mutation and recombination abilities in ß-CoVs resulted in zoonotic diseases in humans. Proteins responsible for viral attachment and replication are highly conserved in ß-CoVs. These conserved proteins have been extensively studied as targets for preventing infection and the spread of ß-CoVs. Peptides are among the most promising candidates for developing vaccines and therapeutics against viral pathogens. The immunostimulatory and viral inhibitory potential of natural and synthetic peptides has been extensively studied since the SARS-CoV outbreak. Food-derived peptides demonstrating high antiviral activity can be used to develop effective therapeutics against ß-CoVs. Specificity, tolerability, and customizability of peptides can be explored to develop potent drugs against ß-CoVs. However, the proteolytic susceptibility and low bioavailability of peptides pose challenges for the development of therapeutics. This review illustrates the potential role of peptides in eliciting an adaptive immune response and inhibiting different stages of the ß-CoV life cycle. Further, the challenges and future directions associated with developing peptide-based therapeutics and vaccines against existing and future ß-CoV pathogens have been discussed.


Subject(s)
Coronavirus Infections , Vaccines , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Humans , Mutation , Peptides/genetics , Peptides/therapeutic use , Vaccines/therapeutic use
5.
Front Immunol ; 13: 770982, 2022.
Article in English | MEDLINE | ID: covidwho-1775662

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike protein (S) of SARS-CoV-2 is a major target for diagnosis and vaccine development because of its essential role in viral infection and host immunity. Currently, time-dependent responses of humoral immune system against various S protein epitopes are poorly understood. In this study, enzyme-linked immunosorbent assay (ELISA), peptide microarray, and antibody binding epitope mapping (AbMap) techniques were used to systematically analyze the dynamic changes of humoral immune responses against the S protein in a small cohort of moderate COVID-19 patients who were hospitalized for approximately two months after symptom onset. Recombinant truncated S proteins, target S peptides, and random peptides were used as antigens in the analyses. The assays demonstrated the dynamic IgM- and IgG recognition and reactivity against various S protein epitopes with patient-dependent patterns. Comprehensive analysis of epitope distribution along the spike gene sequence and spatial structure of the homotrimer S protein demonstrated that most IgM- and IgG-reactive peptides were clustered into similar genomic regions and were located at accessible domains. Seven S peptides were generally recognized by IgG antibodies derived from serum samples of all COVID-19 patients. The dynamic immune recognition signals from these seven S peptides were comparable to those of the entire S protein or truncated S1 protein. This suggested that the humoral immune system recognized few conserved S protein epitopes in most COVID-19 patients during the entire duration of humoral immune response after symptom onset. Furthermore, in this cohort, individual patients demonstrated stable immune recognition to certain S protein epitopes throughout their hospitalization period. Therefore, the dynamic characteristics of humoral immune responses to S protein have provided valuable information for accurate diagnosis and immunotherapy of COVID-19 patients.


Subject(s)
COVID-19 , Antibodies, Viral , Epitopes , Humans , Immunity, Humoral , Immunoglobulin G , Immunoglobulin M , Peptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
6.
Biol Chem ; 403(5-6): 615-624, 2022 Apr 26.
Article in English | MEDLINE | ID: covidwho-1770796

ABSTRACT

The pathogenic agent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into human cells through the interaction between the receptor binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor. Efforts have been made towards finding antivirals that block this interaction, therefore preventing infection. Here, we determined the binding affinity of ACE2-derived peptides to the RBD of SARS-CoV-2 experimentally and performed MD simulations in order to understand key characteristics of their interaction. One of the peptides, p6, binds to the RBD of SARS-CoV-2 with nM affinity. Although the ACE2-derived peptides retain conformational flexibility when bound to SARS-CoV-2 RBD, we identified residues T27 and K353 as critical anchors mediating the interaction. New ACE2-derived peptides were developed based on the p6-RBD interface analysis and expecting the native conformation of the ACE2 to be maintained. Furthermore, we found a correlation between the helicity in trifluoroethanol and the binding affinity to RBD of the new peptides. Under the hypothesis that the conservation of peptide secondary structure is decisive to the binding affinity, we developed a cyclized version of p6 which had more helicity than p6 and approximately half of its K D value.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Binding Sites , Humans , Molecular Dynamics Simulation , Peptides/metabolism , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
7.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Article in English | MEDLINE | ID: covidwho-1768982

ABSTRACT

Adaptive immune recognition is mediated by the binding of peptide-human leukocyte antigen complexes by T cells. Positive selection of T cells in the thymus is a fundamental step in the generation of a responding T cell repertoire: only those T cells survive that recognize human peptides presented on the surface of cortical thymic epithelial cells. We propose that while this step is essential for optimal immune function, the process results in a defective T cell repertoire because it is mediated by self-peptides. To test our hypothesis, we focused on amino acid motifs of peptides in contact with T cell receptors. We found that motifs rarely or not found in the human proteome are unlikely to be recognized by the immune system just like the ones that are not expressed in cortical thymic epithelial cells or not presented on their surface. Peptides carrying such motifs were especially dissimilar to human proteins. Importantly, we present our main findings on two independent T cell activation datasets and directly demonstrate the absence of naïve T cells in the repertoire of healthy individuals. We also show that T cell cross-reactivity is unable to compensate for the absence of positively selected T cells. Additionally, we show that the proposed mechanism could influence the risk for different infectious diseases. In sum, our results suggest a side effect of T cell positive selection, which could explain the nonresponsiveness to many nonself peptides and could improve the understanding of adaptive immune recognition.


Subject(s)
Adaptive Immunity/immunology , Self Tolerance/immunology , T-Lymphocytes/immunology , Databases, Factual , Humans , Lymphocyte Activation/immunology , Peptides/immunology , Peptides/metabolism , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/metabolism
8.
Perm J ; 252021 12 14.
Article in English | MEDLINE | ID: covidwho-1766163

ABSTRACT

This case report describes a successful outcome involving a patient with severe COVID-19 viral pneumonia utilizing a novel therapeutic approach with the glycoprotein IIb/IIIa inhibitor, eptifibatide.


Subject(s)
COVID-19 , COVID-19/drug therapy , Eptifibatide , Humans , Peptides/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex
9.
Int J Mol Sci ; 23(6)2022 Mar 08.
Article in English | MEDLINE | ID: covidwho-1765729

ABSTRACT

Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC50 values in a range from nM to µM values, thus representing an interesting starting point for the further development of potent bioactive compounds on human elastase enzymes.


Subject(s)
Leukocyte Elastase , Peptides , Animals , Humans , Leukocyte Elastase/metabolism , Neutrophils/metabolism , Proteinase Inhibitory Proteins, Secretory/pharmacology , Serine Proteinase Inhibitors/pharmacology
10.
Anal Chem ; 94(14): 5591-5598, 2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1764108

ABSTRACT

High-cost viral nucleic acid detection devices (e.g., qPCR system) are limited resources for developing counties and rural areas, leading to underdiagnosis or even pandemics of viral infectious diseases. Herein, a novel virus detection strategy is reported. Such detection method is enabled by TR512-peptide-based biorthogonal capture and enrichment of commercially available Texas red fluorophore labeled nucleic acid on the functionalized paper. The GST-TR512 fusion protein electrostatically immobilized on the paper is constructed to retain the binding affinity of TR512-peptide toward Texas red fluorophore labeled nucleic acid released in the preamplification process, then the enrichment of analytes enhances fluorescence signal for rapid detection as volume of sample filters through the paper. The method is generally applicable to different nucleic acid preamplification strategies (PCR, RAA, CRISPR) and different virus types (Hepatitis B virus (HBV), African swine fever virus (ASFV), human papillomavirus (HPV), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or 2019 nCoV)). Finally, a full-set virus detection device is developed in house to detect the presence of Hepatitis B virus (HBV) viral gene in patients' blood samples. Taken together, we first apply TR512-peptide in the signal enrichment and the novel detection strategy may offer an inexpensive, rapid, and portable solution for areas with limited access to a standard diagnosis laboratory.


Subject(s)
African Swine Fever Virus , African Swine Fever , COVID-19 , Nucleic Acids , African Swine Fever/diagnosis , African Swine Fever Virus/genetics , Animals , COVID-19/diagnosis , Fluorescent Dyes , Humans , Nucleic Acid Amplification Techniques/methods , Peptides/genetics , SARS-CoV-2/genetics , Sensitivity and Specificity , Swine
11.
PLoS One ; 17(3): e0264700, 2022.
Article in English | MEDLINE | ID: covidwho-1759947

ABSTRACT

Coronaviruses (CoVs) are positive-stranded RNA viruses with short clubs on their edges. CoVs are pathogenic viruses that infect several animals and plant organisms, as well as humans (lethal respiratory dysfunctions). A noval strain of CoV has been reported and named as SARS-CoV-2. Numerous COVID-19 cases were being reported all over the World. COVID-19 and has a high mortality rate. In the present study, immunoinformatics techniques were utilized to predict the antigenic epitopes against 3C like protein. B-cell epitopes and Cytotoxic T-lymphocyte (CTL) were designed computationally against SARS-CoV-2. Multiple Sequence Alignment (MSA) of seven complete strains (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2) was performed to elucidate the binding domain and interacting residues. MHC-I binding epitopes were evaluated by analyzing the binding affinity of the top-ranked peptides having HLA molecule. By utilizing the docked complexes of CTL epitopes with antigenic sites, the binding relationship and affinity of top-ranked predicted peptides with the MHC-I HLA protein were investigated. The molecular docking analyses were conducted on the ZINC database library and twelve compounds having least binding energy were scrutinized. In conclusion, twelve CTL epitopes (GTDLEGNFY, TVNVLAWLY, GSVGFNIDY, SEDMLNPNY, LSQTGIAV, VLDMCASLK, LTQDHVDIL, TTLNDFNLV, CTSEDMLNP, TTITVNVLA, YNGSPSGVY, and SMQNCVLKL) were identified against SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Epitopes, T-Lymphocyte , Molecular Docking Simulation , Peptides , Spike Glycoprotein, Coronavirus , Vaccines, Subunit
12.
Emerg Microbes Infect ; 11(1): 1037-1048, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1752041

ABSTRACT

The coronavirus SARS-CoV-2 is the causative agent for the disease COVID-19. To capture the IgA, IgG, and IgM antibody response of patients infected with SARS-CoV-2 at individual epitope resolution, we constructed planar microarrays of 648 overlapping peptides that cover the four major structural proteins S(pike), N(ucleocapsid), M(embrane), and E(nvelope). The arrays were incubated with sera of 67 SARS-CoV-2 positive and 22 negative control samples. Specific responses to SARS-CoV-2 were detectable, and nine peptides were associated with a more severe course of the disease. A random forest model disclosed that antibody binding to 21 peptides, mostly localized in the S protein, was associated with higher neutralization values in cellular anti-SARS-CoV-2 assays. For antibodies addressing the N-terminus of M, or peptides close to the fusion region of S, protective effects were proven by antibody depletion and neutralization assays. The study pinpoints unusual viral binding epitopes that might be suited as vaccine candidates.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , Epitopes , Humans , Machine Learning , Peptides , Spike Glycoprotein, Coronavirus
13.
Chemistry ; 28(9): e202104182, 2022 Feb 16.
Article in English | MEDLINE | ID: covidwho-1750334

ABSTRACT

Given the emergence of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which particularly threatens older people with comorbidities such as diabetes mellitus and dementia, understanding the relationship between Covid-19 and other diseases is an important factor for treatment. Possible targets for medical intervention include G-quadruplexes (G4Qs) and their protein interaction partners. We investigated the stability and conformational space of the RG-1 RNA-G-quadruplex of the SARS-CoV-2 N-gene in the presence of salts, cosolutes, crowders and intrinsically disordered peptides, focusing on α-Synuclein and the human islet amyloid polypeptide, which are involved in Parkinson's disease (PD) and type-II diabetes mellitus (T2DM), respectively. We found that the conformational dynamics of the RG-1 G4Q is strongly affected by the various solution conditions. Further, the amyloidogenic peptides were found to strongly modulate the conformational equilibrium of the RG-1. Considerable changes are observed with respect to their interaction with human telomeric G4Qs, which adopt different topologies. These results may therefore shed more light on the relationship between PD as well as T2DM and the SARS-CoV-2 disease and their molecular underpinnings. Since dysregulation of G4Q formation by rationally designed targeting compounds affects the control of cellular processes, this study should contribute to the development of specific ligands for intervention.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Humans , Islet Amyloid Polypeptide/metabolism , Peptides , RNA, Viral , alpha-Synuclein/chemistry
14.
Viruses ; 14(3)2022 03 07.
Article in English | MEDLINE | ID: covidwho-1732248

ABSTRACT

Coronaviruses constitute a global threat to the human population; therefore, effective pan-coronavirus antiviral drugs are required to tackle future re-emerging virus outbreaks. Protein kinase CK2 has been suggested as a promising therapeutic target in COVID-19 owing to the in vitro antiviral activity observed after both pharmacologic and genetic inhibition of the enzyme. Here, we explored the putative antiviral effect of the anti-CK2 peptide CIGB-325 on bovine coronavirus (BCoV) infection using different in vitro viral infected cell-based assays. The impact of the peptide on viral mRNA and protein levels was determined by qRT-PCR and Western blot, respectively. Finally, pull-down experiments followed by Western blot and/or mass spectrometry analysis were performed to identify CIGB-325-interacting proteins. We found that CIGB-325 inhibited both the cytopathic effect and the number of plaque-forming units. Accordingly, intracellular viral protein levels were clearly reduced after treatment of BCoV-infected cells, with CIGB-325 determined by immunocytochemistry. Pull-down assay data revealed the physical interaction of CIGB-325 with viral nucleocapsid (N) protein and a group of bona fide CK2 cellular substrates. Our findings evidence in vitro antiviral activity of CIGB-325 against bovine coronavirus as well as some molecular clues that might support such effect. Altogether, data provided here strengthen the rationale of inhibiting CK2 to treat betacoronavirus infections.


Subject(s)
Coronavirus, Bovine , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Casein Kinase II/metabolism , Cattle , Peptides/pharmacology , Phosphorylation
15.
PLoS Comput Biol ; 18(2): e1009833, 2022 02.
Article in English | MEDLINE | ID: covidwho-1731576

ABSTRACT

As sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, ß-trefoils have emerged as an uncommon counterexample: They are an isolated protein lineage for which few, if any, sequence or structure associations to other lineages have been identified. If ß-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the ß-trefoil lineage itself arose de novo. To better understand ß-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both 'ß-trefoil bridging themes' (evolutionarily-related sequence segments) and 'ß-trefoil-like motifs' (structure motifs with a hallmark feature of the ß-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering ß-trefoil sequence segments or structure motifs rather than the ß-trefoil architecture as a whole, as has been done previously. The newly uncovered inter-lineage connections presented here suggest a novel hypothesis about the origins of the ß-trefoil fold itself-namely, that it is a derived fold formed by 'budding' from an Immunoglobulin-like ß-sandwich protein. These results demonstrate how the evolution of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape nature's sewing table.


Subject(s)
Lotus , Immunoglobulin G , Models, Molecular , Peptides/chemistry , Protein Folding
16.
Emerg Microbes Infect ; 11(1): 926-937, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1730559

ABSTRACT

Pandemic influenza virus and SARS-CoV-2 vaiants have posed major global threats to public health. Broad-spectrum antivirals blocking viral entry can be an effective strategy for combating these viruses. Here, we demonstrate a frog-defensin-derived basic peptide (FBP), which broadly inhibits the influenza virus by binding to haemagglutinin so as to block low pH-induced HA-mediated fusion and antagonizes endosomal acidification to inhibit the influenza virus. Moreover, FBP can bind to the SARS-CoV-2 spike to block spike-mediated cell-cell fusion in 293T/ACE2 cells endocytosis. Omicron spike shows a weak cell-cell fusion mediated by TMPRSS2 in Calu3 cells, making the Omicron variant sensitive to endosomal inhibitors. In vivo studies show that FBP broadly inhibits the A(H1N1)pdm09 virus in mice and SARS-CoV-2 (HKU001a and Delta)in hamsters. Notably, FBP shows significant inhibition of Omicron variant replication even though it has a high number of mutations in spike. In conclusion, these results suggest that virus-targeting FBP with a high barrier to drug resistance can be an effective entry-fusion inhibitor against influenza virus and SARS-CoV-2 in vivo.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Animals , COVID-19/drug therapy , Mice , Peptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
17.
Int J Mol Sci ; 23(5)2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1715409

ABSTRACT

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.


Subject(s)
COVID-19/immunology , HLA Antigens/immunology , Polymorphism, Genetic/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , COVID-19/epidemiology , COVID-19/virology , Evolution, Molecular , Gene Frequency , HLA Antigens/genetics , HLA Antigens/metabolism , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Mutation/genetics , Mutation/immunology , Pandemics , Peptides/immunology , Peptides/metabolism , Polymorphism, Genetic/genetics , SARS-CoV-2/physiology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism
18.
Biochimie ; 194: 127-136, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1712463

ABSTRACT

Оligoarginines were recently discovered (Lebedev et al., 2019 Nov) as a novel class of nicotinic acetylcholine receptors (nAChRs) inhibitors, octaoligoarginine R8 showing a relatively high affinity (44 nM) for the α9/α10 nAChR. Since the inhibition of α9/α10 nAChR by α-conotoxin RgIA and its analogs is a possible way to drugs against neuropathic pain, here in a mice model we compared R8 with α-conotoxin RgIA in the effects on the chemotherapy-induced peripheral neuropathy (CIPN), namely on the long-term oxaliplatin induced neuropathy. Tests of cold allodynia, hot plate, Von Frey and grip strength analysis revealed for R8 and α-conotoxin RgIA similar positive effects, expressed most prominently after two weeks of administration. Histological analysis of the dorsal root ganglia sections showed for R8 and RgIA a similar partial correction of changes in the nuclear morphology of neurons. Since α9/α10 nAChR might be not the only drug target for R8, we analyzed the R8 action on rat TRPV1 and TRPA1, well-known nociceptive receptors. Against rTRPV1 at 25 µM there was no inhibition, while for rTRPA1 IC50 was about 20 µM. Thus, involvement of rTRPA1 cannot be excluded, but in view of the R8 much higher affinity for α9/α10 nAChR the latter seems to be the main target and the easily synthesized R8 can be considered as a potential candidate for a drug design.


Subject(s)
Conotoxins , Neuralgia , Receptors, Nicotinic , Animals , Conotoxins/pharmacology , Mice , Neuralgia/chemically induced , Neuralgia/drug therapy , Oxaliplatin/toxicity , Peptides , Rats
19.
ACS Appl Bio Mater ; 5(3): 905-944, 2022 03 21.
Article in English | MEDLINE | ID: covidwho-1705996

ABSTRACT

This review discusses peptide epitopes used as antigens in the development of vaccines in clinical trials as well as future vaccine candidates. It covers peptides used in potential immunotherapies for infectious diseases including SARS-CoV-2, influenza, hepatitis B and C, HIV, malaria, and others. In addition, peptides for cancer vaccines that target examples of overexpressed proteins are summarized, including human epidermal growth factor receptor 2 (HER-2), mucin 1 (MUC1), folate receptor, and others. The uses of peptides to target cancers caused by infective agents, for example, cervical cancer caused by human papilloma virus (HPV), are also discussed. This review also provides an overview of model peptide epitopes used to stimulate non-specific immune responses, and of self-adjuvanting peptides, as well as the influence of other adjuvants on peptide formulations. As highlighted in this review, several peptide immunotherapies are in advanced clinical trials as vaccines, and there is great potential for future therapies due the specificity of the response that can be achieved using peptide epitopes.


Subject(s)
Vaccines, Subunit/administration & dosage , Adjuvants, Immunologic/administration & dosage , Animals , Antigens/immunology , Cancer Vaccines/administration & dosage , Communicable Disease Control , Humans , Neoplasms/therapy , Peptides/immunology
20.
Cell Rep ; 38(10): 110503, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1705992

ABSTRACT

Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.


Subject(s)
COVID-19 , Histocompatibility Antigens Class I , Killer Cells, Natural , Methyltransferases , NK Cell Lectin-Like Receptor Subfamily C , RNA Helicases , SARS-CoV-2 , Viral Nonstructural Proteins , COVID-19/immunology , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/immunology , Methyltransferases/immunology , NK Cell Lectin-Like Receptor Subfamily C/immunology , NK Cell Lectin-Like Receptor Subfamily C/metabolism , Peptides/metabolism , RNA Helicases/immunology , Viral Nonstructural Proteins/immunology
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