Synthesis of Hybrid Peptides and Peptide Mimetics: Structure and Function

Kumar, Santosh (2022) Synthesis of Hybrid Peptides and Peptide Mimetics: Structure and Function. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Santosh Kumar (18RS080)) 18RS080.pdf - Submitted Version Restricted to Repository staff only Download (17MB)

Abstract

This thesis entitled “Synthesis of hybrid peptides and peptide mimetics: Structure and function” discussed the design, synthesis, characterization, conformational analysis, self-association and application of small peptides using proteinogenic and / or non-coded amino acids. The main focus of this thesis are (i) design and synthesis of small peptide by coded as well as non-coded amino acids (ii) study their self-assembly behaviour in solid and solution state (iii) design different supramolecular gel by using small peptides. Here, A new dipeptide as a selective gelator of Cu(II), Zn(II), and Pb(II) in which the various aspects associated with the incorporation of steric constraints into a series of dipeptides have been studied. The self-assembly propensities of the dipeptides carried out with the use of complementary experimental methods enabled us to determine the effect of steric constraints. Gly and Aib containing peptide 1 show a flake-like morphology. The replacement of Gly by L-Phe in peptide 2 increases the steric constraints and results in development of microrods. Peptide 3 with N-phenylglycine and L-Phe has a flower-like morphology, and peptide 4 with N-phenylglycine and L-Tyr has microsphere morphology. The solidstate FT-IR studies show that the peptides self-assemble by hydrogen bonding. From X-ray crystallography, peptide 1 adopts a kink-like conformation and forms a supramolecular anti-parallel sheet-like structure through multiple intermolecular hydrogen bonds. The replacement of Gly by L-Phe helps peptide 2 to adopt an S-shape conformation and self-assemble to form a supramolecular helix in the solid state. Single crystal X-ray diffraction results exhibit that peptide 3 adopts an extended conformation and forms 2D sheet-like matrix through π–π stacking interactions. Moreover, metallogelation of peptide 3 was observed selectively for CuSO₄·5H₂O, ZnSO₄·7H₂O and Pb(OAc)2·3H2O, whereas other metals were not able to form gel. This study revealed a pivotal role played by the phenyl group in the diverse self-assembly of dipeptides. The thesis represents structure-property relationship of a series of synthetic peptides containing coded and non-coded amino acids is presented here. Tyrosine modified terminally protected diphenylalanine (central hydrophobic cluster of Alzheimer’s β-amyloid peptide) exhibits intermolecular hydrogen bonded supramolecular sheet-like structure in crystal. The peptide NPG-Phe-Phe-OMe (1), having a sequence similarity with the diphenylalanine motif, self-aggregates to form entangled fibers. The fibers show green-gold birefringence in Congo red assay. From X-ray diffraction analysis, the tyrosine modified analogues NPG-Phe-Tyr-OMe (2) and NPG-Tyr-Phe-OMe (3) adopt extended conformations and self-aggregate to form sheet-like structures by intermolecular hydrogen bonds and π-π stacking interactions. However, both the tyrosine modified analogues failed to from fibers rather exhibit microspheres like morphology. The analysis of the peptides and the structural information may helpful for de novo design and therapeutics. It also describes the structure-mechanical property correlation of the an α,β-hybrid peptide 1. The α,β- hybrid peptide 1 has L-Phe and methyl-3-aminocrotonate residues and formed monoclinic crystals, with space group P 21/n. From X-ray crystallography analysis, there is a five-member NH⋯N and a sixmember intramolecular NH⋯O=C hydrogen bond and the α,β-hybrid peptide 1 adopts a turn-like conformation, due to the Z-geometry of the methyl-3-aminocrotonate residue. The α,β-hybrid peptide 1 molecules self-assemble by intermolecular N-H⋯O hydrogen bonds and form a supramolecular twisted sheet-like structure which further assembled to form a supramolecular multi-layers structure along the crystallographic b and c directions. However, the α,β-hybrid peptide 1 crystals are sensitive to external stress and brittle in nature. From FE-SEM the crystal appears as a layer by layer structure. The intermolecular interaction energies (kJ/mol) for the α,β-hybrid peptide 1 were calculated using B3LYP/6-31G(d,p) dispersion corrected DFT model. Although the interaction energy is small, there is no scope of slippage due to the interaction of the Boc-t-butyl, Phe side chains and methyl-3- aminocrotonate in the multi-layer sheets. The thesis also describes a series of discotic tripeptides containing a rigid aromatic core and Lphenylalanine. The orientation of the amide bonds yielded variations of the structure and self-assembly properties of the compounds. The aggregation behaviour of the discotic tripeptides was studied by various spectroscopic techniques. The morphology of the resulting aggregates was studied by field emission electron microscopy and atomic force microscopy. These studies showed that the orientation of the amide bonds has a strong influence on the intermolecular interactions, resulting in huge differences in the aggregation properties, and morphology of the discotic tripeptides. Only the C3- symmetric discotic tripeptides formed organogels. The supramolecular aggregation mechanism of Ncentered and C O-centered discotic tripeptides for forming 3-fold intermolecular H-bonded helical column were the same, there was only a smaller enthalpy change due to the occurrence of longer distances for the N–H⋯O C bonds of the N-centered discotic tripeptide. Whereas, the C2-symmetric discotic tripeptides 2 and 3 adopted a 6-fold intermolecular H-bonded dimer structure. Thus, this report presents a valuable approach for the fine-tuning of the discotic tripeptide based functional materials. It also represents that the Porous microspheres from discotic tripeptides was a potential candidates for drug delivery vehicles. The C₃ symmetric discotic tripeptide adopts a supramolecular helical column structure by three fold intermolecular hydrogen bonding interactions as well as face to face π–π stacking interactions. But the C₂ symmetric discotic tripeptide adopts a supramolecular dimer like structure by six-fold intermolecular hydrogen bonding interactions and face to face π–π stacking interactions. Field emission scanning electron microscopy (FE-SEM) revealed that the C₃ symmetric discotic tripeptide exhibits bird nest-like porous microsphere morphology formed by the assembly of the individual columns. However the C₂ symmetric discotic tripeptide forms round clay pitcher like porous microspheres. These porous microspheres have been used as potential carriers for the sustained release of a bacteriostatic antibiotic sulfamethoxazole. The spectroscopic studies as well as the growth inhibition of E. coli reveal that the round clay pitcher-like porous microspheres are more efficient than the bird nest-like porous microspheres for the sustained release of drugs. The report highlights the importance of the self-assembly pattern for the fabrication of advanced functional materials.

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