Deletion analogues of transportan

Several shorter analogues of the cell penetrating peptide, transportan, hav e been synthesized in order to define the regions of the sequence, which ar e responsible for the membrane translocation property of the peptide. Penet ration of the peptides into Bowes melanoma cells and the influence on GTPas e activity in Pin m5F cellular membranes have been tested. The experimental data on cell penetration have been compared with molecular modeling of ins ertion of peptides into biological membranes. Omission of six amino acids f rom the N-terminus did not significantly impair the cell penetration of the peptide while deletions at the C-terminus or in the middle of the transpor tan sequence decreased or abolished the cellular uptake. Most transportan a nalogues exert an inhibitory effect on GTPase activity. Molecular modeling shows that insertion of the transportan analogues into the membrane differs for different peptides. Probably the length of the peptide as well as the location of aromatic and positively charged residues have major impact on t he orientation of peptides in the membranes and thereby influence the cellu lar penetration. In summary, we have designed and characterized several nov el short transportan analogues with similar cellular translocation properti es to the parent peptide, but with reduced undesired cellular activity. (C) 2000 Elsevier Science B.V. All rights reserved.