Backbone N-methylation is common among peptide natural products and has a significant impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was determined by backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (MW = 755) with three N-methyl groups, showed an oral bioavailability of 28% in rat.

The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occurring cyclic peptides, in particular, exhibit a wide variety of unusual and potent biological activities. Many of these compounds penetrate cells by passive diffusion and some, like the clinically important drug cyclosporine A, are orally bioavailable. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of "drug-likeness". Because of their size and complexity, cyclic peptides occupy a chemical "middle space" in drug discovery that may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. However, the relationship between structure and pharmacokinetic (PK) behavior, especially cell permeability and metabolic clearance, in cyclic peptides has not been studied systematically, and the generality of cyclic peptides as orally bioavailable scaffolds remains an open question. This review focuses on cyclic peptide natural products from a "structure-PK" perspective, outlining what we know and don't know about their properties in the hope of uncovering trends that might be useful in the design of novel "rule-breaking" molecules.

The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occurring cyclic peptides, in particular, exhibit a wide variety of unusual and potent biological activities. Many of these compounds penetrate cells by passive diffusion and some, like the clinically important drug cyclosporine A, are orally bioavailable. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of "drug-likeness". Because of their size and complexity, cyclic peptides occupy a chemical "middle space" in drug discovery that may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. However, the relationship between structure and pharmacokinetic (PK) behavior, especially cell permeability and metabolic clearance, in cyclic peptides has not been studied systematically, and the generality of cyclic peptides as orally bioavailable scaffolds remains an open question. This review focuses on cyclic peptide natural products from a "structure-PK" perspective, outlining what we know and don't know about their properties in the hope of uncovering trends that might be useful in the design of novel "rule-breaking" molecules.