Targeting the SARS-CoV2 nucleocapsid protein for potential therapeutics using immuno-informatics and structure-based drug discovery techniques

Kwarteng, Alexander; Asiedu, Ebenezer; Sakyi, Samuel Asamoah; Asiedu, Samuel Opoku

doi:10.1016/j.biopha.2020.110914

Cited by 25 publications

(22 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In an effort to partially overcome this weakness, we applied binding affinity and immunogenicity prediction filters grounded in validated IEDB binding and tetramer studies. Other filtering criteria for T cell epitopes have been evaluated, including allergenicity, antigenicity, stability, and inflammatory/cytotoxic response [ 193 – 195 ]; it remains to be seen if these or other filtering criteria improve T cell epitope selection in SARS-CoV-2. Reassuringly, our selection of T cell-directed vaccine peptides demonstrates significant overlap with the recurrent epitopes identified in eight different studies examining T cell responses in COVID-19 patients (Fig.…”

Section: Discussionmentioning

confidence: 99%

Landscape and selection of vaccine epitopes in SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

Background Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). Methods We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. Results From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. Conclusions Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

show abstract

Section: Discussionmentioning

confidence: 99%

Landscape and selection of vaccine epitopes in SARS-CoV-2

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Moreover, for the ease of the readers, all the details related to the 125 CCnRs, 92 MHC-I and MHC-II restricted T-cell epitopes and 61 B-cell epitopes are provided in the supplementary as an excel file , the link of which is given in Table S6. Additionally, a list of MHC-I and MHC-II restricted T-cell and B-cell epitopes for SARS-CoV-2 as collected from different sources in the literature like [26] , [27] , [17] , [28] , [16] , [15] , [20] , [24] , [23] , [29] , [30] , [31] , [32] , [33] , [25] are reported in Table 5 . For space constraint, 3 of each MHC-I and MHC-II restricted T-cell and B-cell epitopes from each paper are mentioned in this table while the list of all the MHC-I and MHC-II restricted T-cell and B-cell epitopes are given in the supplementary as an excel file as given in Table S6 .…”

Section: Resultsmentioning

confidence: 99%

“…Apart from Spike, they have identified epitopes derived from NSP3, 3CL-pro, NSP8, NSP9 and NSP10 proteins to be highly likely candidates for vaccine design. There are other works like [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] as well pertaining to epitope identification in SARS-CoV-2 for vaccine design.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of Indian SARS-CoV-2 genomes to identify T-cell and B-cell epitopes from conserved regions based on immunogenicity and antigenicity

Ghosh

Sharma

Saha

et al. 2021

International Immunopharmacology

View full text Add to dashboard Cite

“…Mefuparib hydrochloride, CVL218, a Poly [ADP-ribose] polymerase 1 (PARP1) inhibitor have shown to exhibit effective inhibitory activity against SARS-CoV-2 replication without apparent cytopathic effect in in-vitro and in-silico studies [84]. Zidovudine triphosphate, an anti-HIV drug, acts as a potential inhibitor of the N-terminal domain of SARS-CoV2 N-protein based on docking and simulation research, and can be considered to repurpose for therapeutic options to fight COVID-19 [85]. Out of 13 molecules analyzed for the molecular simulation study on SARS-CoV-2 nucleocapsid protein, 3 (Varespladib, MK-5108, Stepronin) have been found to be show inhibitory activity on SARS-CoV-2 N protein with high docking score [86].…”

Section: Structural Protein Inhibitorsmentioning

confidence: 99%

Repurposed Therapeutic Strategies towards COVID-19 Potential Targets Based on Genomics and Protein Structure Remodeling

Singh¹,

Singh²,

Dubey³

2022

Biotechnology to Combat COVID-19

View full text Add to dashboard Cite

Target recognition is important for the identification of drugs with a high target specificity and/or for the development of existing drugs that could be replicated for the treatment of SARS-CoV-2 infections. Since SARS-CoV-2 is a pathogen recently discovered, no specific medicines have been identified or are available at present. The scientific community had proposed list of current drugs with therapeutic potential for COVID-19 on the basis of genomic sequence information coupled with protein structure modeling, posing an effective and productive therapeutic approach for repurposing existing drugs. The possible therapeutics for the treatment of COVID-19 involves a wide range of alternatives, encompassing nucleic acid-based treatments directed at the expression of genes of viruses, cytokine therapy, genetic engineered and vectored antibodies, and different formulations of vaccines. The future prospective in the treatment approaches the exploration of antiviral therapy, such as screening of prevailing molecules or libraries, testing of existing broad-spectrum antiviral medications, modern drug discovery focused on genomic knowledge and biochemical properties of various coronaviruses to create new targeted drugs.

show abstract

Targeting the SARS-CoV2 nucleocapsid protein for potential therapeutics using immuno-informatics and structure-based drug discovery techniques

Abstract: Graphical abstract

Cited by 25 publications

References 74 publications

Landscape and selection of vaccine epitopes in SARS-CoV-2

Landscape and selection of vaccine epitopes in SARS-CoV-2

Genome-wide analysis of Indian SARS-CoV-2 genomes to identify T-cell and B-cell epitopes from conserved regions based on immunogenicity and antigenicity

Repurposed Therapeutic Strategies towards COVID-19 Potential Targets Based on Genomics and Protein Structure Remodeling

Contact Info

Product

Resources

About