Peptidyl spacer

One of the most successful conjugate polymer systems was developed by Duncan and Kopecek (25). The polymer carrier used in their system is poly [N(2-hydroxypropyl) methacrylamide] a biocompatible polymer that was originally developed as a plasma extender. They have evaluated a number of polymer conjugated drugs for cancer chemotherapy with interesting results. The attachment of the drug is through a peptidyl spacer pendent to the polymer backbone. These peptides links are stable in aqueous media but are readily hydrolyzed intracellularly... 

An instructive and quite fortunate example of cooperative binding (Figure 6) was reported on the interaction of the peptide antibiotic vancomycin with the glycopeptide 4 mimicking a portion of the bacterial cell waU. The terminal o-Ala-o-Ala peptide attached to the saccharide backbone via a lactoyl-peptidyl spacer, which occurs in two copies in compound 4, is prone for binding into the cleft offered by vancomycin. The evaluation of the ITC titration... 

Peptidyl spacer was used for releasing the parent dmg from the conjugate by lysosomal enzymes of cathepsins after its uptake into cells. The longer retention of the conjugate in bloodstream should lead it to a more preferential tumor-accumulation, in proportion to its levels of tumor vascular permeability, and the control of dmg-release should bring out the best in the... 

The peptidyl spacer (GGFG) provided slow releases of both DX-8951 and G-DX-8951 in vitro (tumor homogenates and cathepsins) and in vivo the slow dmg-release in tumor tissue is extremely advantageous to cytotoxicity of the time-dependent antitumor dmg, DX-8951. A high steric hindrance of the bulky DX-8951 moiety was found to be responsible for the slow releases of both dmgs from CM-Dex-PA-GGFG-DX-8951, while the GGFG spacer showed a fast dmg-release with such a less bulky dmg as doxombicin. 

Dimcan, et al. " have investigated a number of copolymers having a backbone based on iV-(2-hydroxpropyl)methacrylamide (HPMA, 37). Briefly, sidechains containing various amino acid (peptidyl) spacers are introduced onto the HPMA polymer. These peptidyl sidechains include Gly-Gly and Gly-Phe-Leu-Gly that contain carboxylate or amino end-groups that are reacted with cisplatin. 

Figure 5 Starting from natural mRNA, a cDNA library (A blue) is produced and like ribosomal display, the cDNA is transcribed into mRNA (B) with no stop codons. The 3 -end of each mRNA molecule is ligated to a short synthetic DNA linker (C) and sometimes a polyethyleneglycol spacer, which terminates with a puramycin molecule (small red sphere). The ligation is stabilized by the addition of psoralen (green clamp), which is photoactivated to covalently join both strands. Addition of crude polysomes or purified ribosomes (D) results in translation of the mRNA into protein, but the ribosome stalls at the mRNA-DNA junction. Since there are no stop codons, release factors cannot function and instead the puromycin enters the A-site of the ribosome (A). Because puramycin is an analog of tyrosyl-tRNA, the peptidyl transferase subunit catalyzes amide bond formation between the puromycin amine and the peptide carboxyl terminus, but is unable to hydrolyze the amide link (which should be an ester in tyrosyl-tRNA) to release the dimethyladenosine. The ribosome is dissociated to release the mRNA-protein fusion (E), which is protected with complementary cDNA using RT-PCR (F). The mRNA library can then be selected against an immobilized natural product probe (G), nonbinding library members washed away and the bound mRNA (H) released with SDS. PCR amplification of the cDNA provides a sublibrary (A) for another round of selection or for analysis/ sequencing.

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