Peptides conformationally constrained mimics

HIV-1 protease (HIV-1 PR) Non-peptide, C2-symmetric cyclic urea derivatives were designed de novo to fit the HlV-i PR active site. These novel, conformationally-constrained inhibitors feature a diol functionality that interacts with the catalytic aspartates while an urea oxygen mimics a structural water mediating substrate interactions with the enzyme flap. The required absolute configuration at four chiral centers was correctly predicted. Potent, bioavailable clinical candidates emerged from this work. i37 ... 

One strategy to control folding is to direct folds by introduction of S-hairpins, turns which are often associated with Pro incorporation in a polypeptide sequence. Constrained turn mimics have previously been employed in investigations of the active conformation of peptides. Clearly, from the above discussion of CyP and... 

In this paper we report the synthesis of an antibody mimic based on calix[4]arene linked to four constrained peptide loops.. . . Calix[4]arene was chosen as the core scaffold, as it is readily available and can be locked into the semirigid cone conformation by alkylation of the phenol groups. This results in a projection of the para-substituents onto the same side of the ring to form a potential binding domain. (p. 2681)... 

While this monocyclic reverse-turn template clearly mimics the backbone conformation and side-chain presentations of p- and "y-tums quite well, one concern with such a large macrocycle is that the relatively flexible peptide backbone conformations are strongly influenced by the side-chain-side-chain interactions, as investigated by NMR solution structure (Fig. 29.11). ° We therefore needed a new type of turn mimetic bearing a constrained and rigid skeleton which could potentially enhance binding and/or improve bioavailability. Based on the conformational analyses of several heterobicyclic systems, we envisioned... 

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