There is no doubt that without the ability of nature to form very stable aggregates of small molecules, or to form well-defined secondary, tertiary and even quaternary structures of macromolecules, life as we know it could not exist. The folding of polypeptide chains into secondary and eventually a bewildering array of tertiary structures results in protein molecules that are responsible for most of the biological interactions and functions found in nature. A logical next step is to mimic nature and to create nonbiological structures, involving intramolecular folding of unnatural molecules that are capable of mimicking or antagonizing the biological action(s) of a natural parent peptide, the so called: PEPTIDOMIMETICS. The development of these chemical model systems provides valuable insights into biomolecular structure and interactions by allowing researchers to simplify, isolate, and manipulate aspects of the complex molecular machinery of living systems. This thesis reports our efforts towards the design and synthesis of new peptidomimetics that act as secondary structure inducing elements with respect to the growing peptide chain (such as the b-hairpin mimics, discussed in Chapter II) or that are able to establish a defined secondary structure with biological targets. (i.e. the molecular tongs discussed in Chapter III). In Chapter II, a practical synthesis of a new bifunctional diketopiperazine scaffold, formally derived from the cyclization of L-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. The scaffold bears a carboxylic acid functionality and an amino functionality in a cis relationship, which were used to grow peptide sequences. Conformational analysis of these peptidomimetic sequences reveals the formation of b-hairpin mimics and a reverse turn of the peptide chain. Synthetic peptides and peptidomimetics, containing the arginine-glycine-aspartate (RGD) sequence, have been used as inhibitors of integrin-ligand interactions. In many cases, the RGD sequence is combined with a secondary structure inducing element to form cyclic peptidomimetics. Therefore, the diketopiperazine scaffold was used to synthesise a cyclic peptidomimetic containing the RGD sequence that was tested as a selective ligand for the avb3 integrin receptor. In Chapter III, new peptidomimetics were introduced in molecular tongs for inhibiting HIV-1 protease dimerization. HIV-1 protease (PR) is a homodimer of two identical 99-amino acid subunits in which the active site is generated by self-assembly of these subunits. Remarkably, the antiparallel b-sheet formed by interdigitation of N- and C-terminal strands of each protease monomer, which contributes over 75% to the stabilization force of the dimer, is found relatively free of mutations. By targeting this highly conserved dimerization interface, we demonstrated that HIV-1 protease dimer is disrupted with loss of activity by constrained molecular tongs that are able to establish a stable b-sheet structure with the N- and C-terminal of one PR monomer, mimicking the 4-stranded b-sheet structure of the protease dimer. Herein, we describe the design, synthesis, and enzyme inhibitory activity against wild-type HIV-1 PR, of new molecular tongs containing hydrazide-based peptidomimetic fragments in both arms, as well as, new naphthalene-based scaffolds bearing hydrophilic groups.

Synthesis, conformational analysis and biological evaluation of peptidometics acting as B-sheet inducers(2008).

Synthesis, conformational analysis and biological evaluation of peptidometics acting as B-sheet inducers.

2008-01-01

Abstract

There is no doubt that without the ability of nature to form very stable aggregates of small molecules, or to form well-defined secondary, tertiary and even quaternary structures of macromolecules, life as we know it could not exist. The folding of polypeptide chains into secondary and eventually a bewildering array of tertiary structures results in protein molecules that are responsible for most of the biological interactions and functions found in nature. A logical next step is to mimic nature and to create nonbiological structures, involving intramolecular folding of unnatural molecules that are capable of mimicking or antagonizing the biological action(s) of a natural parent peptide, the so called: PEPTIDOMIMETICS. The development of these chemical model systems provides valuable insights into biomolecular structure and interactions by allowing researchers to simplify, isolate, and manipulate aspects of the complex molecular machinery of living systems. This thesis reports our efforts towards the design and synthesis of new peptidomimetics that act as secondary structure inducing elements with respect to the growing peptide chain (such as the b-hairpin mimics, discussed in Chapter II) or that are able to establish a defined secondary structure with biological targets. (i.e. the molecular tongs discussed in Chapter III). In Chapter II, a practical synthesis of a new bifunctional diketopiperazine scaffold, formally derived from the cyclization of L-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. The scaffold bears a carboxylic acid functionality and an amino functionality in a cis relationship, which were used to grow peptide sequences. Conformational analysis of these peptidomimetic sequences reveals the formation of b-hairpin mimics and a reverse turn of the peptide chain. Synthetic peptides and peptidomimetics, containing the arginine-glycine-aspartate (RGD) sequence, have been used as inhibitors of integrin-ligand interactions. In many cases, the RGD sequence is combined with a secondary structure inducing element to form cyclic peptidomimetics. Therefore, the diketopiperazine scaffold was used to synthesise a cyclic peptidomimetic containing the RGD sequence that was tested as a selective ligand for the avb3 integrin receptor. In Chapter III, new peptidomimetics were introduced in molecular tongs for inhibiting HIV-1 protease dimerization. HIV-1 protease (PR) is a homodimer of two identical 99-amino acid subunits in which the active site is generated by self-assembly of these subunits. Remarkably, the antiparallel b-sheet formed by interdigitation of N- and C-terminal strands of each protease monomer, which contributes over 75% to the stabilization force of the dimer, is found relatively free of mutations. By targeting this highly conserved dimerization interface, we demonstrated that HIV-1 protease dimer is disrupted with loss of activity by constrained molecular tongs that are able to establish a stable b-sheet structure with the N- and C-terminal of one PR monomer, mimicking the 4-stranded b-sheet structure of the protease dimer. Herein, we describe the design, synthesis, and enzyme inhibitory activity against wild-type HIV-1 PR, of new molecular tongs containing hydrazide-based peptidomimetic fragments in both arms, as well as, new naphthalene-based scaffolds bearing hydrophilic groups.
2008
Synthesis, conformational analysis and biological evaluation of peptidometics acting as B-sheet inducers(2008).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2090293
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