158306-85-5Relevant academic research and scientific papers
Biodegradable microspheres. 17. Lysosomal degradation of primaquine- peptide spacer arms
Borissova,Stjarnkvist,Karlsson,Sjoholm
, p. 256 - 262 (1995)
The pharmacological activity of drugs bound to lysosomotropic drug carriers will depend on the rate of release of the drugs from the drug- carrier complex. We have now studied the enzymatic release of primaquine (PQ) from two groups of peptide-PQ derivatives by their incubation with rat liver lysosomal fraction. The derivatives have the general structure NH2-X-Leu- Ala-Y-PQ and are intended to be coupled via their free α-amino group to starch microparticles. In the first group, Y was varied, being Leu, Tyr, Lys, or Asp, while X was Ala. In the second one, X was varied, being Ala, Tyr, Lys, or Asp, while Y was Leu. Thus, a systematic study of the significance of the varying amino acid composition of the tetrapeptides, which can serve as spacer arms in the microparticle-drug complexes, for the lysosomal release of PQ was possible. In addition, some ε-aminocaproic acid-PQ derivatives, which lack a free α-amino group, were incubated. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of these derivatives. The pattern and rate of degradation of all PQ derivatives was followed by HPLC analysis. The results obtained show that endopeptidases, as well as mono- and diaminopeptidases, degrade the derivatives. PQ cannot be cleaved directly from the derivatives by any carboxypeptidase-like enzyme. Asp peptides are digested slowly in the lysosomal fraction. The temporal aspects of reactions were quantitated using a kinetic model, in which first-order rate constants of all the steps of each peptide degradation sequence were estimated simultaneously.
Biodegradable microspheres. 16. Synthesis of primaquine-peptide spacers for lysosomal release from starch microparticles
Borissova,Lammek,Stjarnkvist,Sjoholm
, p. 249 - 255 (2007/10/02)
Classical procedures of peptide synthesis were applied to synthesize four groups of compounds, and analytical methods were developed for each of them. Two of the groups are tetrapeptide derivatives of the antileishmanial drug primaquine (PQ), with general structure NH2-X-Leu-Ala-Y-PQ. In the first group, Leu, Tyr, Lys, and Asp were used in the Y position, while X was Ala. In the second group, Ala, Tyr, Lys, and Asp were used in the X position, while Y was Leu. The derivatives are intended to be coupled, via their free α-amino group, to polyacryl starch microparticles, lysosomotropic drug carriers developed in our laboratory. Thus, a systematic study of the significance of the varying amino acid composition of the tetrapeptide spacer arm for the rate of lysosomal enzymatic release of PQ can be possible. A third group, composing ε-aminocaproic acid-PQ derivatives which lack a free α-amino group, was synthesized. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of these derivatives. To allow HPLC analysis of the pattern of degradation of tetrapeptide-PQ derivatives, some shorter peptide-PQ derivatives (group four) were prepared as well.
