Abstract
This study presents a rational design approach to discovery synthetic peptide vaccine candidates from endogenous proteins for chronic non-infectious diseases immunological therapeutics. The approach described the screening of key antigenic amino acid residues of the interleukine-13, which is up-regulated expression in asthma, followed by the development of immunological helper epitope peptides via an integrative computational and experimental method. Notably, this totally synthetic peptide vaccine was capable of stimulating humoral immune responses much stronger than those of parental antigenic peptides by enhancing the efficiency of antigen presentation, and had effective treatment in mouse asthma models. Our approach offers new possibilities to discovery therapeutic peptide vaccine candidates for chronic non-infectious diseases, with highly consolidated in silico and animal disease models for fast iterative screening.
Highlights
Asthma is an atopic disorder with features that include airway inflammation and airway hyperresponsiveness (AHR). [1] Dysfunctional regulation of interleukins (IL) often associates with different pathogenesis processes of asthma. [2-4] Nowadays, the administrations of soluble receptors or monoclonal antibodies of interleukins are efficient treatment approaches for asthma and other allergic disorders. [5] these therapeutic approaches possess some shortcomings, e.g. limited half-life, frequent and inconvenient injections, relatively large dosage and costly treatment charge
These results suggested that the molecular dynamics (MD) trajectories of the three complexes were stable, and the conformations of epitopes were maintained so it was reasonable to do the experimental validation
We firstly synthesized and evaluated several vaccine candidates V1, V2 and V3, which contained different IL-13 antigenic epitopes (E1, E2 and E3, respectively) conjugated to a T helper epitope derived from diphtheria toxin (Ditox[382-401], AYNFVESIINLFQVVHNSYN) (Figure 3A)
Summary
Asthma is an atopic disorder with features that include airway inflammation and airway hyperresponsiveness (AHR). [1] Dysfunctional regulation of interleukins (IL) often associates with different pathogenesis processes of asthma. [2-4] Nowadays, the administrations of soluble receptors or monoclonal antibodies (mAb) of interleukins are efficient treatment approaches for asthma and other allergic disorders. [5] these therapeutic approaches possess some shortcomings, e.g. limited half-life, frequent and inconvenient injections, relatively large dosage and costly treatment charge. [2-4] Nowadays, the administrations of soluble receptors or monoclonal antibodies (mAb) of interleukins are efficient treatment approaches for asthma and other allergic disorders. Mepolizumab (IL-5 mAb) has been approved by FDA (Food and Drug Administration) for the treatment of adults with severe asthma; its high therapeutic costs brought the manufacturer GSK was condemned by the public immediately. Based on IL-13 is to be one of the most important modulators in asthma pathology, vaccines, monoclonal antibodies and soluble receptors to block IL-13 have been developed, which are mainly keen on developing recombinant protein antagonists to block IL-13 signal of target cells or neutralize the functional of extracellular IL13. [6, 7] these approaches presented many disadvantages, such as high-dose requirements, the high expenses of facilities, the stability of the antagonists, et al Based on IL-13 is to be one of the most important modulators in asthma pathology, vaccines, monoclonal antibodies and soluble receptors to block IL-13 have been developed, which are mainly keen on developing recombinant protein antagonists to block IL-13 signal of target cells or neutralize the functional of extracellular IL13. [6, 7] these approaches presented many disadvantages, such as high-dose requirements, the high expenses of facilities, the stability of the antagonists, et al
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