Template mimetics

While the a-helix of L-a-peptides and the (M)-3i4 helix of the corresponding peptides have opposite polarity and helicity (see Section 2.2.3.1), the inserhon of two CH2 groups in the backbone of L-a-amino acids leave these two hehx parameters unchanged, both the a-helix and the 2.614-hehx of the resulting y" -peptides being right-handed and polarized from N to C terminus. In view of these similarities, the y-peptide hehcal fold might prove useful as a template to elaborate functional mimetics of bioachve a-polypeptides. 

Although biologically active helical y-peptides have not been reported so far, the striking structural similarities (polarity and helicity) between the a-helix of L-a-peptides and the (P)-2.6i4-hehx of y-peptides suggest that the 2.614-helical backbone might prove useful as a template for elaborating functional mimetics of a-helical surfaces and intervening in protein-protein interactions. 

In light of the importance of the / -turn motif in peptide and protein recognition, and the design and synthesis of bioactive small molecules, / -turn mimetics has attracted considerable attention. Seebach and coworkers have shown recently that low molecular weight open-chain / - and y-peptides designed to promote turn formation can be used as templates for mimicking the a-peptide hormone somatostatin. 

Chemical libraries of /3-turn mimetics, among them highly saturated pyrazino[l,2-tf]pyrazines, were synthesized and patented as biologically useful compounds <2001W02001/000210>. Solid-phase syntheses starting from substituted a,/3-unsaturated ester templates provided differently substituted saturated heterocyclic systems, among them saturated 2,4,8-trisubstituted-pyrazino[l,2- ]pyrazine-l,6-diones <2003W02003/013740>. 

Compound 508 (PNRI-299), a small molecule /3-strand mimetic template compound, is active as an inhibitor of the multifunctional activating protein factor 1 (AP-1). PNRI-299 has demonstrable effects on the reduction of API-driven transcription and beneficial pharmacological effects in a mouse asthma model. The compound affects the expression of leukotriene C4 (LTC4) synthase, a crucial enzyme for the formation of the cysteinyl leukotrienes <2003PNA1169, 2004MI211>. 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

Figure 3. Discovery of Urotensin II GPCR antagonist by peptide mimetic approaches. 3D models of the NMR solution structure of cyclic peptide derivatives were used as templates for virtual 3D pharmacophore searches and resulted into non-peptidic hits. ° (Figure reproduced with permission from review of Klabunde and Messier. )...

Low molecular weight heparins, heparin fractions, or other sulfated polysaccharides still have the same or a similar complexity as heparin and are, therefore, not regarded as heparinoid mimetics only compounds with one defined carbohydrate backbone serving as a template for sulfates will be discussed in this context. 

Membrane-mimetic compartments have provided a viable means for generating monodispersed catalytic particles [500], In particular, reversed micelles and microemulsions have been used extensively as hosts. A complete summary of work reported on the in situ generation of catalysts in membrane-mimetic media, including publications up to 1987, has been produced [500] and, therefore, will not be reiterated here. Attention will be focused on more recent research utilizing monolayers, bilayer lipid membranes (BLMs), Langmuir-Blodgett (LB) films, zeolites, and clay particles as membrane-mimetic templates. 

Cheng, S. Tarby, C. M. Comer, D. D. Williams, J. P. Caporale, L. H. Myers, P. L. Boger, D. L. A Solution-Phase Strategy for the Synthesis of Chemical Libraries Containing Small Organic Molecules A Universal and Dipeptide Mimetic Template, Bioorg. Med. Chem. 1996, 4, 727. 

The immunodominant portion of the malaria circumsporozoite surface protein contains a tetrapeptide motif (-Asn-Pro-Asn-Ala-), tandemly repeated almost 40 times. Bisang et aft165 incorporated the (I-turn mimetic 131 into the cyclic template 132 (Scheme 48). BALB/c mice... 

There are few examples of C-terminal helix mimetics and, while their utility has been considered uncertain,11361 successful helix induction has been described using tetra-hydronaphthalene compounds represented by 16.11351 Templated peptide 17, for example, demonstrates 81% helix by CD while control peptide 18 exhibits only 50% helix under the same conditions (Scheme 7). For the preparation of tetrahydronaphthalene templates and their attachment to peptides, see refs.1134,1351... 

In addition to incorporating the 4-(2-aminoethyl)dibenzofuran-6-propanoic acid template into small peptides where a reverse turn is desired, we have also recently incorporated this template into a mini-protein called the PIN WW domain. WW domains have a three-stranded antiparallel p-sheet structure that mediates intracellular protein-protein interactions. 31 Substitution of this 3-turn mimetic into loop 1 of the PIN WW domain leads to a folded, three-stranded, antiparallel p-sheet structure with a stability indistinguishable from that of the all a-amino acid sequence. The template-incorporated PIN WW domain (11) was synthesized by an Fmoc-based solid-phase peptide synthesis strategy (Scheme 8), utilizing N-Fmoc-protected 4-(2-aminoethyl)dibenzofuran-6-propanoic acid 10. 11 The synthesis of 10, similar to that of 8, has been published.1 1 ... 

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