IMPIPS: The Immune Protection-Inducing Protein Structure Concept in the Search for Steric-Electron and Topochemical Principles for Complete Fully-Protective Chemically Synthesised Vaccine Development

Abstract

Determining immune protection-inducing protein structures (IMPIPS) involves defining the stereo-electron and topochemical characteristics which are essential in MHC-p-TCR complex formation. Modified high activity binding peptides (mHABP) were thus synthesised to produce a large panel of IMPIPS measuring 26.5 ±3.5Å between the farthest atoms fitting into Pockets 1 to 9 of HLA-DRβ1* structures. They displayed a polyproline II-like (PPIIL) structure with their backbone O and N atoms orientated to establish H-bonds with specific residues from HLA-DRβ1*-peptide binding regions (PBR). Residues having specific charge and gauche+ orientation regarding p3χ1, p5χ2, and p7χ1 angles determined appropriate rotamer orientation for perfectly fitting into the TCR to induce an appropriate immune response. Immunological assays in Aotus monkeys involving IMPIPS mixtures led to promising results; taken together with the aforementioned physicochemical principles, non-interfering, long-lasting, protection-inducing, multi-epitope, multistage, minimal subunit-based chemically-synthesised peptides can be designed against diseases scourging humankind.

TCR-contacting residues orientation and HLA-DRβ* binding preference determine long-lasting protective immunity against malaria

“…That goal was achieved when a large number of highly immunogenic protection-inducing peptide structures (IMPIPS) [13] fulfilled those requirements when used as individual epitopes in primary challenges.…”

“…600 MHz spectrometer 1 H-NMR 3D structures were determined with RP-HPLC-purified IMIPS; their sequential connectivities and dihedral angles have already been described [13,14,16,17,18,19] . Only χ1 angle degrees of residues considered TCR contacting (positions p2, p5, p8) regarding their binding in the HLA-DR peptide binding region (PBR) are described, based on their predicted binding to HLA-DR molecules.…”

Recent advances in the development of a chemically synthesised anti-malarial vaccine

“…cHABPs having short, compact or right-handed a-helical structure with 1.5 A per residue, 3.6 residues per pitch (~12 A between the 9 residues the PBR can accommodate), inter-atomic H-bonds and f = -60 , -90 , y = -40 , -60 angle limits did not fit into the HLA-DRb1*PBR groove. Furthermore, cHABPs having long, extended structure b-sheets, folded b-turns (having 2 residues per turn and H-bonds between i + 1 and i + 2) or random structures were too long or had inadequate structure to fit into the HLA-DRb1*PBR [81, [100][101][102]. It has been reported that endogenous or variable antigenic peptides associated with HLA-DRb* alleles adopt a PPII L conformation and become firmly anchored into their PBR [100].…”

“…In fact, we have recently reported that a mixture formed by CSP-and MSP-1-derived mHABPs having such P3 and P7 rotamer orientation did not block, interfere or compete with or suppress the protective immune response induced by just Spz-or Mrz-derived mHABPs, which we have called immune protection-inducing protein structures (IMPIPS) and should be the subunit components of any new chemically synthesised vaccine [81,102].…”

“…Grey arrows indicate TCR foot diagonal print orientation. angles, which determine proper rotamer orientation for perfectly fitting into the MHC II--IMPIPS--TCR complex to induce an appropriate immune response [102].…”