The backbone constitution drives passive permeability independent of side chains in depsipeptide and peptide macrocycles inspired by ent -verticilide.

Autor: Thorpe MP; Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Nashville TN 37235-1822 USA jeffrey.n.johnston@vanderbilt.edu., Smith AN; Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Nashville TN 37235-1822 USA jeffrey.n.johnston@vanderbilt.edu., Blackwell DJ; Department of Medicine, Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Vanderbilt University Medical Center Medical Research Bldg IV, Room 1265, 2215B Garland Ave Nashville TN 37232-0575 USA., Hopkins CR; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center Omaha NE 68198 USA., Knollmann BC; Department of Medicine, Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Vanderbilt University Medical Center Medical Research Bldg IV, Room 1265, 2215B Garland Ave Nashville TN 37232-0575 USA., Akers WS; Pharmaceutical Sciences Research Center, College of Pharmacy, Lipscomb University Nashville TN 37204 USA., Johnston JN; Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Nashville TN 37235-1822 USA jeffrey.n.johnston@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2024 Aug 15. Date of Electronic Publication: 2024 Aug 15.
DOI: 10.1039/d4sc02758b
Abstrakt: The number of peptide-like scaffolds found in late-stage drug development is increasing, but a critical unanswered question in the field is whether substituents (side chains) or the backbone drive passive permeability. The backbone is scrutinized in this study. Five series of macrocyclic peptidic compounds were prepared, and their passive permeability was determined (PAMPA, Caco-2), to delineate structure-permeability relationships. Each series was based on the cell-permeable antiarrhythmic compound ent -verticilide, a cyclic oligomeric depsipeptide (COD) containing repeating ester/ N -Me amide didepsipeptide monomers. One key finding is that native lipophilic ester functionality can impart a favorable level of permeability, but ester content alone is not the final determinant - the analog with highest P app was discovered by a single ester-to- N -H amide replacement. Furthermore, the relative composition of esters and N -Me amides in a series had more nuanced permeability behavior. Overall, a systematic approach to structure-permeability correlations suggests that a combinatorial-like investigation of functionality in peptidic or peptide-like compounds could better identify leads with optimal passive permeability, perhaps prior to modification of side chains.
Competing Interests: The authors declare no competing financial interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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