Peptide motifs for cell-surface intervention: application to anti-infective and biopharmaceutical development

The discovery of new antimicrobial and anticancer drugs, and overcoming the problem of resistance to current anti-infective and anticancer drug therapies require innovation in the pharmaceutical and scientific research community. A further challenge of drug design is to make the therapeutic agent specific, long lasting, of minimal toxicity, and affordable. Microbial and cancer cell surfaces present molecular features that can differentially prefocus drugs within the human host. This property can localize drugs near cell-surface targets, thereby reducing opportunities for adverse effects, or the emergence of drug resistance caused by intracellular drug and target modification and by the induction of drug efflux pumps. The solubility demands on cell-surface targeting drugs should also be less stringent than for those drugs requiring transmembrane transport or internalization in order to reach intracellular targets. Cationic peptides have provided an increasingly important research focus in this regard. Although the cationic antimicrobial peptides are distributed widely in nature and provide localized primary defenses against microbial attack, the susceptibility of L-peptides to proteolysis and the known properties of successful antimicrobials have led to a focus on circularized peptides, D,L-peptides, and peptides containing unusual amino acids. New on the scene as lead antifungal agents are D-octapeptides and their derivatives that were developed from a combinatorial library produced through solid-phase peptide synthesis protocols. These peptides contain an amidated C-terminal tri-arginine motif, which confers membrane impermeability and focuses the peptides near the fungal cell surface. To date, the octapeptides and their derivatives also require some aromaticity, preferably the indole ring of tryptophan. In some cases, a single 4-methoxy-2,3,6-trimethylbenzenesulfonyl moiety remaining on the peptide after incomplete cleavage of the peptide from the solid phase produces a peptide with activity, whereas the parent shows little or no activity in the screen. Recent research advances that support the polycationic cell surface approach include the RGD (Arg-Gly-Asp) tripeptide and its mimetics, as well as aminoglycoside arginine drugs (e.g. neomycin coupled to small arginine polymers) and prodrugs. In the case of polycationic peptides, D-peptides could be used for intravenous injection and direct-surface drug applications, but mimetics will probably be needed for oral delivery.