Peptides acids into

Peptides and proteins are formed by linking successive amino acids into chains or rings. The order (sequence) and types of amino acids determine the chemical and physical properties of peptides and proteins. 

The succinimide derivative (234) can be used in peptide synthesis for conversion of amino acids into their succinimide esters (235 Scheme 41) (79CL1265). 3-Substituted mercapto-1,2-benzisothiazole 1,1-dioxides (236) have been recommended as an odourless means of storage of thiols. The latter are readily regenerated by the action of piperidine (81CL1457). 

Figure 28.7 A representation of protein biosynthesis. The codon base sequences on mRNA are read by tRNAs containing complementary anticodon base sequences. Transfer RNAs assemble the proper amino acids into position for incorporation into the growing peptide.

Since our original aPNA publication, there have been other reports of the incorporation of nucleobases into a-helical peptides. Mihara and coworkers reported that a-hehcal coiled-coiled peptides could be stabilized by base pairs between complementary y-nucleobase-a-aminobutanoic acids [78] They have also reported that the incorporation of such nucleoamino acids into a-hehcal segments of HIV-1 Rev and HIV-1 nucleocapsid protein can result in increased binding affinity and specificity to HIV-1 RRE RNA and SL3 RNA respectively [79, 80]. 

A systematic replacement of any amino acid in the sequence for photoreac-tive analogues allows a photoaffinity scanning of the binding interface. Since solid-phase synthesis is limited in the length of the peptide, Schultz et al. developed a sophisticated method which makes it possible to incorporate unnatural amino acids into large peptide sequences. The photoreactive amino acid was linked to transfer RNA, which inserted the amino acid into the required position by in vivo translation [44]. 

JM Humphrey, AR Chamberlin. Chemical synthesis of natural product peptides coupling methods for the incorporation of noncoded amino acids into peptides. Chem Rev 97, 2243, 1997. 

Replacement of coded L-amino acids with d-amino acids is a common strategy in peptide drugs. However, it must be stressed that D-amino acids are far from unknown in nature and can even be found in animal peptides, where they are usually formed from L-amino acids by a post-translational reaction [208], It appears that this mechanism increases the structural diversity of products that can be synthesized from one gene, thus increasing the scope of evolution by natural selection. In other words, the incorporation of D-amino acids into peptides is a strategy discovered by evolution and rediscovered by chemists. 

Upon encountering a stop codon on the mRNA, the ribosome will halt incorporation of further amino acids into the polypeptide as there is no tRNA complementary to a stop codon (UAG, UGA, UAA). In order to liberate the polypeptide, the ester bond between the peptide and the tRNA residing in the P site has to be hydrolyzed — a reaction that is also catalyzed in the peptidyltransferase center. It is critical for protein synthesis that peptide release is tightly coupled to the presence of a stop codon in the decoding center to avoid premature termination resulting in shortened, nonfunctional proteins. Both functions, recognizing the stop codon and triggering... 

Based on our current understanding of ribosomal protein synthesis, several strategies have been developed to incorporate amino acids other than the 20 standard proteinogenic amino acids into a peptide using the ribosomal machinery . This allows for the design of peptides with novel properties. On the one hand, such a system can be used to synthesize nonstandard peptides that are important pharmaceuticals. In nature, such peptides are produced by nonribosomal peptide synthetases, which operate in complex pathways. On the other hand, non-natural residues are a useful tool in biochemistry and biophysics to study proteins. For example, incorporation of non-natural residues by the ribosome allows for site-specific labeling of proteins with spin labels for electron paramagnetic resonance spectroscopy, with... 

This bond wiE later supply energy to make a peptide bond linking the amino acid into a protein. 

Chemoselective ligation of peptides using the free amino terminal as nucleophile and a thiobenzyl thioester C-terminal amino acid as electrophile provides an efficient approach to the synthesis of proteins with several hundred residues [30]. From this perspective the introduction of non-natural amino acids into proteins becomes a possibility rather than a problem and chemoselective ligation is thus a prospect for the future for the incorporation of new functionality. 

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