Author:
Ochoa Rodrigo,Lunardelli Victoria Alves Santos,Rosa Daniela Santoro,Laio Alessandro,Cossio Pilar
Abstract
Epitopes that bind simultaneously to all human alleles of Major Histocompatibility Complex class II (MHC II) are considered one of the key factors for the development of improved vaccines and cancer immunotherapies. To engineer MHC II multiple-allele binders, we developed a protocol called PanMHC-PARCE, based on the unsupervised optimization of the epitope sequence by single-point mutations, parallel explicit-solvent molecular dynamics simulations and scoring of the MHC II-epitope complexes. The key idea is accepting mutations that not only improve the affinity but also reduce the affinity gap between the alleles. We applied this methodology to enhance a Plasmodium vivax epitope for multiple-allele binding. In vitro rate-binding assays showed that four engineered peptides were able to bind with improved affinity toward multiple human MHC II alleles. Moreover, we demonstrated that mice immunized with the peptides exhibited interferon-gamma cellular immune response. Overall, the method enables the engineering of peptides with improved binding properties that can be used for the generation of new immunotherapies.
Funder
Universidad de Antioquia
Departamento Administrativo de Ciencia, Tecnología e Innovación
Fundação de Amparo à Pesquisa do Estado de São Paulo
Subject
Immunology,Immunology and Allergy
Cited by
7 articles.
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