Intestinal permeability of cyclic peptides: common key backbone motifs identified.
Insufficient oral bioavailability is considered as a key limitation for the widespread development of peptides as therapeutics. While the oral bioavailability of small organic compounds is often estimated from simple rules, similar rules do not apply to peptides, and even the high oral bioavailability that is described for a small number of peptides is not well understood. Here we present two highly Caco-2 permeable template structures based on a library of 54 cyclo(-D-Ala-Ala(5)-) peptides with different N-methylation patterns. The first (all-trans) template structure possesses two β-turns of type II along Ala(6)-D-Ala(1) and Ala(3)-Ala(4) and is only found for one peptide with two N-methyl groups at D-Ala(1) and Ala(6) [(NMe(1,6)]. The second (single-cis) template possesses a characteristic cis peptide bond preceding Ala(5), which results in type VI β-turn geometry along Ala(4)-Ala(5). Although the second template structure is found in seven peptides carrying N-methyl groups on Ala(5), high Caco-2 permeability is only found for a subgroup of two of them [NMe(1,5) and NMe(1,2,4,5)], suggesting that N-methylation of D-Ala(1) is a prerequisite for high permeability of the second template structure. The structural similarity of the second template structure with the orally bioavailable somatostatin analog cyclo(-Pro-Phe-NMe-D-Trp-NMe-Lys-Thr-NMe-Phe-), and the striking resemblance with both β-turns of the orally bioavailable peptide cyclosporine A, suggests that the introduction of bioactive sequences on the highly Caco-2 permeable templates may result in potent orally bioavailable drug candidates.
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Department Chemie, Lichtenbergstrasse 4, 85747 Garching, Germany.
Johannes G
JG
Beck
Jayanta
J
Chatterjee
Burkhardt
B
Laufer
Marelli Udaya
MU
Kiran
Andreas O
AO
Frank
Stefanie
S
Neubauer
Oded
O
Ovadia
Sarit
S
Greenberg
Chaim
C
Gilon
Amnon
A
Hoffman
Horst
H
Kessler
D018938:Caco-2 Cells; D004151:Dipeptides / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008745:Methylation; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics*; D010539:Permeability; D017433:Protein Structure, Secondary
D004151:Dipeptides; D010456:Peptides, Cyclic; C002956:alanylalanine