Fig. 1: Effect of O to S substitution on the lipophilicity and permeability of peptides. | Nature Communications

Fig. 1: Effect of O to S substitution on the lipophilicity and permeability of peptides.

From: An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides

Fig. 1

a Octanol-water partition coefficient (logD7.4) of oxo (grey), thioamidated (yellow), and N-methylated (blue) dipeptides with the common sequence FX. The “X” residues are mentioned at the bottom of the bars. b logD7.4 of the cyclic pentaalanine (8) and hexaalanine (9) peptides with their respective thioamidated analogs indicated by small letters, which denote the site of thioamidation. c AlogP of cyclo(-D-Leu1-Leu-Leu-D-Pro-Tyr-Leu6-)(10), cyclo(-Ile1-Ala-Ala-Phe-Pro-Ile-Pro7-)(11), and cyclo(-D-Leu1-Leu-D-Pro-D-Leu-Leu-D-Ala-Pro-Leu8-)(12). The small letters denote the site of thioamidation in the individual scaffolds. d logD7.4 of 10, 11, 12 and their respective thioamidated analogs. e Membrane permeability of the macrocyclic peptides determined by the PAMPA (Pe). Propranolol and PC (cyclo(-D-Leu1-Leu-D-Leu-Pro-Tyr-Leu6))31 were used as the markers for transcellular transport. f The plot of logD7.4 vs. PAMPA permeability of all the 24 macrocyclic peptides. The blue shaded region highlights the lipophilicity zone of macrocycles with permeability > 2.5 ×10−6 cm/s; for clarity only the mean values are plotted. n = 3 ± SEM. Each bar represents mean values of three biological replicates: dots are individual data points. Statistical significance of the analogs was measured against the (all-amide) parent molecule by a one-tailed unpaired t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, ns (non-significant) > 0.05. p (1 vs 1a, 1b) = 0.0339, 0.0045; p (2 vs 2a, 2b) = 0.0003, 0.002; p (3 vs 3a, 3b) = 0.0213, 0.0257; p (4 vs 4a, 4b) = 0.001, 0.0603; p (5 vs 5a, 5b) = 0.1513, 0.0716; p (6 vs 6a, 6b) = 0.0084, 0.0418; p (7 vs 7a, 7b) = 0.021, 0.0105; p (8 vs 8a, 8b 8c, 8d, 8e) = 0.002, <0.0001, 0.0001, 0.0006, 0.0005; p (9 vs 9a, 9b 9c, 9d, 9e, 9f) = 0.0308, 0.0310, 0.0267, 0.0308, 0.0237, 0.0154; p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0011, 0.0003, 0.0014, 0.0009, 0.0003, 0.0005; p (11 vs 11a, 11b, 11c, 11d, 11e, 11f, 11g) = <0.0001, 0.0050, <0.0001, 0.0016, <0.0001, <0.0001, 0.0027; p (12 vs 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h) = 0.0002, <0.0001, 0.0007, <0.0001, <0.0001, 0.0022, 0.0014, <0.0001 for logD7.4. p (10 vs 10a, 10b, 10c, 10d, 10e, 10f) = 0.0019, 0.0239, 0.0503, 0.0815, 0.0005, 0.016; p (11 vs 11a, 11b, 11c, 11d, 11e, 11f, 11g) = 0.0019, 0.4776, 0.0114, 0.4596, 0.0299, 0.0207, 0.3486; p (12 vs 12a, 12b, 12c, 12d, 12e, 12f, 12g, 12h) = 0.0839, 0.3126, 0.0344, 0.0017, 0.0130, 0.0199, 0.0123 for Pe by PAMPA. Source data are provided as a Source Data file.

Back to article page