Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds

Abstract

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.

Oral aktive Peptide: Gibt es ein Patentrezept?

“…[99a] Im Gegensatz dazu verhindert diestarkeBasizitätder Guanidinium-Gruppe desA rg einenp assiven Tr ansport vollständig.I mF allv on zellpenetrierenden Peptiden verbessert diem çgliche Bildung einer zweizähnigenS alzbrücked er Guanidinium-Gruppe in Anwesenheit vong eeignetenG egenioneni mV ergleich zu primärenA minen wie Lyso derO rn dieA ufnahme. geben an,d asse inep olareS eitenkette beid er Permeabilität [118] toleriert wird. Einei nteressante Beobachtung bezüglichdes Einflussesvon Lysmachte die GruppeumBorchardt, welche berichtete, dass der Einbau vonLys in einT ripeptid die Permeabilitätverhindert,wohingegendie selbe Substitutionin einH exapeptid dieP ermeabilitäti mV ergleichz um Derivat, dasdas neutrale Asnenthält,nicht beeinflusst.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Furthermore, the accessibility of polar atoms in a molecule could be decreased if IMHBs are established. This may influence desolvation equilibria and facilitate the passage of molecules through low dielectric environments [216,217,218]. While geometric preferences for the formation of IMHBs have been described based on experimental evidence [67], the presence of stabilizing IMHBs are normally debated based on thermodynamics grounds, especially in high dielectric environments.…”

Orally Active Peptides: Is There a Magic Bullet?

“…In the case of cellpenetrating peptides,t he possible formation of ab identate salt bridge by the guanidinium group in contrast to the primary amine of the Lyso rO rn in the presence of suitable counterions improves the uptake. [94] Hickey et al claimed that one polar side chain is tolerated for permeability [118] and this finding fits to the omnipresent Ty ri nt he permeable lipophilic peptides examined by the Lokey group. [94] Hickey et al claimed that one polar side chain is tolerated for permeability [118] and this finding fits to the omnipresent Ty ri nt he permeable lipophilic peptides examined by the Lokey group.…”

“…[86] On the other hand, reports indicate the participation of at ransporter, suggested by different uptake rates of cyclic hexaalanine enantiomers,which indicates the participation of achiral structural element in their transport and different flux ratios in Caco-2 membranes. [126] As tudy of af urther refunctional- hiding side-chain polarity i) Thr is apolar amino acid that is well-tolerated in bioavailable peptides [99a,116] ii)replacementofThr by Ser led to decreased permeability and, thus, the b-methyl group seems to orient the hydroxy group to form an intramolecular hydrogen bond and to shield the polarity iii)2-pyridinealanine can hide the side-chain polarity in amanner similar to Thr, [155] but attempts to modify permeable cyclic peptides resulted in lower permeability [150] [99a, 116] exocyclic peptide bond i) introducedbyaziridine-aldehyde-based macrocyclization, followed by nucleophilic attack by isocyanide and hydrolysis [118] ii)used to optimize the hydrogen bonding network, thereby reducing the polarity and flexibility of ap eptide iii)has aturn-inducing effect [107b] [118] lipophilic prodrug charge masking (LPCM) approach i) shields charges through esterase-labile protecting groups that enable uptake of the peptide [119] ii)prodrug concepts for cyclizing peptides, which release alinear peptide after cleavage, have been developed [156] iii)positive and negative charges can be protectedbyenzymatically labile groups, such as in arecently publishedc yclic peptide (24) iv) the biologically active compound is releasedi nto the blood stream and can bind to surface receptors, such as integrins; [115] this concept was adopted for cyclic peptides derived from dabigatran [157] [ 115,156] lipidation i) increases lipophilicity through aliphaticc hains ii)increases plasma stability iii)binds to serum albumin, prolongingthe duration of systemic circulation [158] iv) forms self-assembling oligomeric macromolecules, enhances enzymatic degradation [159] v) its effect on bioavailability strongly depends on the fatty acid chain length [160] vi)t he modification with amyristoyl group (n = 12) improved the oral bioavailability of the peptide c(MyD 4-4) by af actor of > 50 to F = 47 AE 16 % [161] [162] glycosylation i) affects the backbone structure of peptides [163] ii)improves half-life against enzymatic degradation [164] iii)glycosylated sandostatin (d(+)-maltose) shows a10-fold greater oral effect than the nonglycosylated derivative [165] iv) glycosylated endomorphin-1 (27)s hows a700-fold increase in memb...…”