Form and Function in Cyclic Peptide Natural Products: A Pharmacokinetic Perspective

Abstract

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.

Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides

“…28 We also observed a very large solvent-dependent conformational effect on aqueous solubility among synthetic analogues of the natural product sanguinamide A. 24 Yet although conformational flexibility has been observed in CSA as well as some other natural products, 29 the effect of flexibility per se on physicochemical properties has not been studied in these natural systems.…”

“…This phenomenon has been well described for cyclosporine A and has been attributed to other natural products by inference. 29 Although it is often discussed in reference to the behavior of CSA and other bRo5 compounds, 28 the effect of conformational flexibility on ADME properties has been studied in only a handful of model systems. 16,24,41 To explore the conformation of 3 in a polar environment we performed NMR experiments in DMSO, which was chosen because of its high dielectric constant and its ability to effectively solubilize lipophilic peptides.…”

The Unusual Role of Pro in Cu(II) Binding by His2-Cyclopentapeptide

“…Moreover, they are also more thermally stable than their linear analogs. Head-to-tail cyclization implies increased lipophilicity and membrane permeability [ 9 , 10 ]. The cyclic analogs of conotoxin (potential treatment of pain) and chlorotoxin (imaging of brain tumors) are more stable than their linear counterparts [ 11 , 12 ].…”

Molecular networking as a dereplication strategy for monitoring metabolites of natural product treated cancer cells

“…A considerable amount of pharmacological activities of natural products is involved in their intracellular processes. 19 However, to probe the interaction between the mammalian cell and compounds derived from natural products with the current omics platforms requires prior understanding of the genomics or proteomics of the target cells. [20][21][22][23][24][25] As many bioactivities of medicinal fungi are associated with the multiplex interactions of the entire consortium of specialized metabolites with cells, a high-throughput approach to visualize and dereplicate the natural product uptake and the subsequent metabolic changes in mammalian cells is essential for providing further insights into the pharmacological mechanisms of bioactive compounds.…”