Figure 1.

“To be steady as a rock and always trembling.”¹⁴⁴ α-Amanitin and cyclosporine A provide contrasting lessons from natural products. Both are head-to-tail cyclic peptides, and deviations from the 20 proteinogenic amino acids are shown in red. α-Amanitin is locked into a single conformation by virtue of a sulfone-indole intramolecular cross-link. This protects it from proteolytic degradation despite having a largely unmodified peptide backbone and appears to promote gut absorption and transport into liver cells by organic anion transport proteins (OATPs).¹² Cyclosporine, by contrast, survives digestive proteases by virtue of its highly N-methylated backbone. It can change conformations in order to form intramolecular hydrogen bonds in nonpolar environments.²³ This is hypothesized to promote passive diffusion through plasma membranes.