Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules.
J Med Chem
; 60(5): 1665-1672, 2017 03 09.
Article
in En
| MEDLINE
| ID: mdl-28059508
ABSTRACT
Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (â¼800 Da < MW < â¼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Membrane Permeability
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2017
Document type:
Article
Affiliation country:
United States