Abstract
This protocol describes the manual solid-phase synthesis of linear peptoids that contain two differently functionalized cationic monomers. In this procedure amino functionalized 'lysine' and guanido functionalized 'arginine' peptoid monomers can be included within the same peptoid sequence. This procedure uses on-resin (N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) or Dde protection, orthogonal conditions to the Boc protection of lysine monomers. Subsequent deprotection allows an efficient on-resin guanidinylation reaction to form the arginine residues. The procedure is compatible with the commonly used submonomer method of peptoid synthesis, allowing simple peptoids to be made using common laboratory equipment and commercially available reagents. The representative synthesis, purification and characterization of two mixed peptoids is described. The evaluation of these compounds as potential anti-infectives in screening assays against Leishmania mexicana is also described. The protozoan parasite L. mexicana is a causative agent of cutaneous leishmaniasis, a neglected tropical disease that affects up to 12 million people worldwide.
Highlights
Peptoids are a class of peptide-mimetics that offer similar properties to peptides and as such are increasingly being investigated for medicinal and materials applications
Peptoids are commonly synthesized using the submonomer method pioneered by Zuckermann et al, where peptoid monomers can be built by sequential haloacetylation of an amine functionality attached to a solid support and subsequent displacement of the halogen using a primary amine.[1]
Our group has recently developed an adaptation to this submonomer method to allow lysine- and arginine-type peptoid residues to be included within the same peptoid sequence for the first time.[2]
Summary
Peptoids (or poly-N-substituted glycines) are a class of peptide-mimetics that offer similar properties to peptides and as such are increasingly being investigated for medicinal and materials applications. Resistance to existing drugs is an emerging and serious problem so new treatments are desperately needed to effectively treat leishmaniasis in the future.[12,13,14,15,16] In these antimicrobial applications, peptoids are often designed to be amphipathic with a mixture of cationic and hydrophobic monomers.[3,4] This can give peptoids a degree of selectivity towards bacterial cells, reduce toxicity to mammalian cells, and to improve their activity as molecular transporters.[17,18,19,20] The majority of the anti-infective peptoids in the literature contain cationic side chains that are exclusively comprised of either amino functionalized lysine-type monomers or arginine-type residues. It is expected that this method will aid the synthesis of amphipathic peptoids by the peptoid community in the future
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