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crc press - E-Lib FK UWKS

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142 Cell-Penetrating Peptides: Processes and Applications<br />

ABSTRACT<br />

The goal of this review is to summarize previously published work on the design<br />

and biological activity of a family of guanidinium peptoid transporters that differ in<br />

the length of their side chains and to compare these results with a more recently<br />

designed family of transporters containing non-α-amino acids, i.e., variations along<br />

the backbone. The latter group of peptides differs by the spacing of the arginine<br />

subunits along the peptide backbone. When these analogs were assayed for cellular<br />

uptake, the most important feature was shown to be not the nature of the substituted<br />

amino acid, but rather the distance between each of the arginines.<br />

When results of the two studies were compared a very similar pattern was<br />

observed. By increasing the conformational freedom of either the side chains of the<br />

peptoids or the backbone of peptides by the addition of methylene units, a significant<br />

enhancement in the rate of cellular uptake of the transporter was seen. Even though<br />

the conformational flexibility of peptoids and peptides is very different, addition of<br />

methylenes in either the backbone or the side chain results in enhanced cellular<br />

uptake, arguing that the flexibility of the guanidine headgroups can be accomplished<br />

in either of these ways. Typically, the biological activity of most biological ligands,<br />

particularly those functioning as inhibitors, increases with conformational restriction<br />

as preorganization in the form of the bound conformer favors tighter binding. The<br />

enhanced activity associated with increased conformational mobility observed for<br />

molecular transporters is in agreement with a dynamic transport system in which<br />

turnover rather than tightness of binding is critical for function.<br />

7.1 INTRODUCTION<br />

Biological barriers have evolved to prevent entry of xenobiotics into tissues and<br />

cells. However, these same barriers often limit or preclude uptake, and therefore the<br />

therapeutic benefit, of a variety of drugs. Consequently, most drugs must be restricted<br />

in physical properties to allow cellular and tissue uptake. This requirement greatly<br />

limits the universe of potential therapeutics to a very small number of compounds.<br />

The studies reviewed below were directed toward the goal of enhancing or enabling<br />

delivery of drugs through biological barriers by conjugation to transporter molecules.<br />

Oligomers of arginine composed of six or more amino acids, either alone or when<br />

covalently attached to a variety of small molecules, cross biological membranes very<br />

effectively by an as yet undefined mechanism. 1 The chirality of the amino acid subunits<br />

in the arginine oligomers does not affect transport activity. In addition, a variety of other<br />

nonpeptide, guanidine-rich molecular transporters that do not share the composition or<br />

the spacing of a peptide have been shown to exhibit transport into cells.<br />

The guanidine headgroup of arginine appears to be the key structural unit for<br />

cellular uptake. 1,2 The rate of uptake is dependent on both the concentration of the<br />

oligomers and their guanidine content, with a greater rate observed as the length of the<br />

peptide is increased up to approximately 15 residues. Oligomers beyond this length<br />

enter cells less effectively, precipitate serum proteins, and exhibit cellular cytotoxicity<br />

at high micromolar concentrations. Detailed kinetic analyses demonstrated that nonamers<br />

of arginine were significantly more effective at crossing biological membranes than

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