Synthesis and biological evaluation of new inhibitors of HIV-1 protease dimerization and \u3b1V\u3b23-integrin atagonists with pptidomimetic Structures.

Abstract

Despite the versatile and interesting function of peptides in biological systems, metabolic instability and poor bioavailability make them ineffective as orally administered drugs. Due to these limitations, peptidomimetic compounds are preferred as drug candidates. This thesis deals with the design and the synthesis of peptidomimetics. In the Chapter I, peptidomimetics were introduced in molecular tongs as dimerization inhibitors of wild-type and mutated HIV-1 Proteases. 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 fsheet formed by interdigitation of N- and C-terminal strands of each protease monomer, which contributes over 75 % to the stabilizing 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 based on naphthalene scaffold. We describe here the synthesis, the enzyme inhibitory activity against wild-type and mutated HIV-1 PR, of new molecular tongs containing amino acid mimetic fragments in one or two strands. In the Chapter II, diketopiperazine scaffold was introduced in cyclic RGD peptidomimetics, as new integrin inhibitors. Synthetic peptides and peptidomimetics, containing the arginine-glycine-aspartate (RGD) motif, have been widely used as inhibitors of integrin-ligand interactions to study cell growth, adhesion, migration and differentiation. In many cases, the RGD sequence is combined with a secondary structure inducing element to form cyclic peptidomimetics. In this project, a few cyclic peptidomimetics containing a bifunctional diketopiperazine (DKP) unit (cis and trans) and the RGD sequence, were prepared by solution phase peptide synthesis, and tested as selective ligands for the integrins \u3b1v\u3b23 and \u3b1v\u3b2