Peptide-derived peptidomimetic inhibitors

A common feature of nearly all X-ray crystal complexes between HIVPR and peptide-derived peptidomimetic inhibitors (PPIs) is the presence of a tetracoordinated structural water molecule tightly bound between the inhibitor molecule and the flexible beta strands or flaps of the HIVPR dimer. This ubiquitous water molecule accepts two hydrogen bonds from backbone amide bonds of flap residues IleSO and IleSO and donates two hydrogen bonds to suitable acceptors, typically carbonyl groups, which flank the transition state isostere of the peptide mimetic inhibitor (Fig. 3a) [31]. Potent... 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

An outstanding example in peptidomimetic design evolved from these studies. Truncation and conformational restriction of a reduced isostere of the parent peptide substrate, followed by systematic replacement of the peptide-like side-chains provided the potent non-peptidic inhibitor (111)(Fig. 15.46) (207). This approach highlights the transition from a peptide-derived structure to a compound with no apparent resemblance to the original peptide. 

Alternatively, a recognition site in close proximity to the ATP-binding site can be targeted with an oligopeptide as the reporter ligand, whose sequence is derived from the activating kinase MKK3b in case of p38 MAP kinase [82], The inhibition of the protein-protein interaction with a small peptide could serve as a template for peptidomimetic inhibitor development [83, 84],... 

Yan LZ, Dawson PE (2001) Synthesis of peptides and proteins without cysteine residues by native chemical ligation combined with desulfurization. J Am Chem Soc 123(4) 526-533 Yin H, Frederick KK, Liu D et al. (2006) Arylamide derivatives as peptidomimetic inhibitors of calmodulin. Org Lett 8(2) 223-225... 

Due to their substantial size and peptidic nature, inhibitors from this class were not suitable for clinical application. Nevertheless, the structural information derived from many crystal structures of peptidic inhibitors bound to the HIV PR active site was critical for subsequent modeling and design of the next generation of peptidomimetic and nonpeptidic inhibitors of HIV PR. 

JIP-1 is a JNK pathway scaffold protein essential for JNK activation in some systems. Like many substrates, JIP-1 binds to JNK in the region generally called the common docking site in MAPKs (28). With the identification of the key residues of JNK required for interaction with the kinase interaction motif of JIP-1, small peptide inhibitors (TI-JIP RPKRPTTLNLF) derived from JIP have been described (29). As expected, TI-JIP was found to be competitive with respect to the phosphoaccep-tor substrate c-Jun and to exhibit noncompetitive inhibition with respect to ATP. It is not yet clear whether peptidomimetics or small molecule inhibitors that might have clinical applicability will be developed using information from JNK-JIP-1 interactions. 

Many peptidomimetics derived from the design of TSA inhibitors, molecules designed according to the hypothesis provided by Pauling (77) and implemented by Wolfenden (78,79). TSA protease inhibitors are stable analogs of the tetrahedral intermediate for peptide bond hydrolysis that inhibit the enzyme (Fig. 15.18). The first successful commercial application was the development of captopril (38) by Ondetti et al. (80), and many applications have been reported over the past quarter century. 

Peptoids [22] form a particular promising class of oligomeric peptidomimetics, which consists of A-substituted-glycine derivatives. Thus, the concepts to translate a particular peptide sequence, in this case CAAX to a corresponding peptoid sequence is a perfectly suitable approach to obtain potential famesyl inhibitors. This approach was adopted by... 

As indicated previously, many pharmacologically interesting target receptors exhibit large surface spanning areas where it has been notoriously difficult to find small molecules as inhibitors. For this purpose peptoids, peptides and especially peptidomimetics derived fixtm structural information of the targets can be valuable tools for lead finding (cf. Chapter 2). 

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

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