Side chain peptide moieties

Polymers Containing Side Chain Peptide Moieties... 

The first example of the use of a controlled radical polymerization technique for the construction of polymers with side chain peptide moieties was... 

Amoxaclllln (Table 38.5). Amoxicillin is a close analogue of ampicillin, in which a para-phenolic hydroxyl group has been introduced into the side-chain phenyl moiety. This adjusts the isoelectric point of the drug to a more acidic value, and this is believed to be partially responsible, along with the intestine peptide transporter, for the enhanced blood levels obtained with amoxicillin as compared to ampicillin itself (Table 38.6). Better oral absorption (74-92%) leads to less disturbance of the normal Gl flora and, therefore, less drug-induced diarrhea. The antimicrobial spectrum and clinical uses of amoxicillin are approximately the same as those of ampicillin itself, and it is presently one of the most popular drugs in North America. 

Aspaityl proteinases are proteinases that utilize the terminal carboxyl moiety of the side chain of aspartic acid to effect peptide bond hydrolysis. 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

There is only a small selection of nonprotein amino acids that contain carbonyl groups in the form of ketone, aldehyde, and carboxylic acid moieties, as part of the side chain. The examples given in Table 6 are components of nonribosomal peptides isolated from bacteria or fungi and siderophores from bacteria. The biosynthesis of these amino acids is not clear however, some of the amino acids with carboxylic acid side chains may be traced back to the L-a-amino acids aspartic acid and glutamic acid. 

Included in this category of compounds are one example of a substrate analogue containing an 7V-ketoalkyl scissile bond surrogate moiety (213), and a number of non-substrate analogue peptides Table 8.19) [176, 209-214]. Some of the latter compounds contain a Cys residue whose side-chain may be interacting with the active site Zn(II) atom. All of these compounds are... 

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