Conserved Binding Regions Provide the Clue for Peptide-Based Vaccine Development: A Chemical Perspective

Abstract

Synthetic peptides have become invaluable biomedical research and medicinal chemistry tools for studying functional roles, i.e., binding or proteolytic activity, naturally-occurring regions’ immunogenicity in proteins and developing therapeutic agents and vaccines. Synthetic peptides can mimic protein sites; their structure and function can be easily modulated by specific amino acid replacement. They have major advantages, i.e., they are cheap, easily-produced and chemically stable, lack infectious and secondary adverse reactions and can induce immune responses via T- and B-cell epitopes. Our group has previously shown that using synthetic peptides and adopting a functional approach has led to identifying Plasmodium falciparum conserved regions binding to host cells. Conserved high activity binding peptides’ (cHABPs) physicochemical, structural and immunological characteristics have been taken into account for properly modifying and converting them into highly immunogenic, protection-inducing peptides (mHABPs) in the experimental Aotus monkey model. This article describes stereo–electron and topochemical characteristics regarding major histocompatibility complex (MHC)-mHABP-T-cell receptor (TCR) complex formation. Some mHABPs in this complex inducing long-lasting, protective immunity have been named immune protection-inducing protein structures (IMPIPS), forming the subunit components in chemically synthesized vaccines. This manuscript summarizes this particular field and adds our recent findings concerning intramolecular interactions (H-bonds or π-interactions) enabling proper IMPIPS structure as well as the peripheral flanking residues (PFR) to stabilize the MHCII-IMPIPS-TCR interaction, aimed at inducing long-lasting, protective immunological memory.

Plasmodium falciparum Blood Stage Antimalarial Vaccines: An Analysis of Ongoing Clinical Trials and New Perspectives Related to Synthetic Vaccines

“…The blood-stage antimalarial vaccine candidates’ immunogenicity results described here (mainly based on P. falciparum protein conserved regions) have indicated that although moderate Ab titers are induced after a first immunization, they do not induce long-lasting protective immunity. This is consistent with our research demonstrating that, although conserved regions are functionally important for target cell binding, they are poorly recognized by host immune system due to being located far from the highly polymorphic regions used by the parasite as an evasion mechanism to distract the immune system (Patarroyo et al, 2017b); such polymorphic regions are immunodominant but confer just strain-specific immunity (Hisaeda et al, 2005; Curtidor et al, 2017).…”

“…This methodology has enabled testing and selecting mHABP derived from parasite life cycle stages, which has led to promising results in obtaining a highly immunogenic and protection-inducing antimalarial vaccine (Garcia et al, 2007; Rodriguez et al, 2008; Bermúdez et al, 2012; Curtidor et al, 2017). Chemically synthesized vaccines’ main advantages include their high yield, reproducibility, purity (free of contaminants, such as endotoxins), lack of secondary adverse reactions, being able to synthesize unlimited amounts and stability at room temperature for long periods of time (not requiring cold chain) (Bermúdez et al, 2008; Skwarczynski and Toth, 2016).…”

Preliminary Evaluation of the Safety and Immunogenicity of an Antimalarial Vaccine Candidate Modified Peptide (IMPIPS) Mixture in a Murine Model

“…Peptide Synthesis and Purification. Twenty-three polymer peptides (Table 1) were modified following previously reported principles [32,33,40,41] to render them immunogenic and then synthesised using solid-phase multiple peptide synthesis following the tert-butyloxycarbonyl (t-Boc) synthesis strategy described by Merrifield [42] and modified by Houghten [43]. All peptides were derived from fully conserved and functionally relevant regions of the corresponding proteins.…”

Assessing Peptide Binding to MHC II: An Accurate Semiempirical Quantum Mechanics Based Proposal

“…Therefore, understanding MHC class II binding enables designing pharmaceutical vaccines against infectious diseases. Studying MHC-DR binding prediction has special relevance developing a peptide-based malaria vaccine which is our group’s main goal. − …”