Cyclization
and selected backbone N-methylations are found to
be often necessary but not sufficient conditions for peptidic drugs
to have a good bioavailability. Thus, the design of cyclic peptides
with good passive membrane permeability and good solubility remains
a challenge. The backbone scaffold of a recently published series
of cyclic decapeptides with six selected backbone N-methylations was designed to favor the adoption of a closed conformation with β-turns and four transannular hydrogen bonds.
Although this conformation was indeed adopted by the peptides as determined
by NMR measurements, substantial differences in the membrane permeability
were observed. In this work, we aim to rationalize the impact of discrete
side chain modifications on membrane permeability for six of these
cyclic decapeptides. The thermodynamic and kinetic properties were
investigated using molecular dynamics simulations and Markov state
modeling in water and chloroform. The study highlights the influence
that side-chain modifications can have on the backbone conformation.
Peptides with a d-proline in the β-turns were more
likely to adopt, even in water, the closed conformation
with transannular hydrogen bonds, which facilitates transition through
the membrane. The population of the closed conformation
in water was found to correlate positively with PAMPA log P
e.
Permeability and oral bioavailability of macrocyclic peptides still represent difficult challenges in drug discovery. Despite the recognized potential of macrocyclic peptides as therapeutics, their use is still restricted to extracellular targets and intravenous administration. Indeed, macrocyclic peptides generally suffer from limited proteolytic stability, high clearance, and poor membrane permeability, and this leads to the absence of systemic exposure after oral administration. To overcome these limitations, we started to investigate the development of a general cyclic decapeptide scaffold that possesses ideal features for cell permeability and oral exposure. On the basis of a rigid hairpin structure, the scaffold design aimed to decrease the overall polarity of the compound, thereby limiting the energetic cost of NH desolvation and the entropy penalty during cell penetration. The results of this study also demonstrate the importance of rigidity for the β-turn design regarding clearance. To stabilize the scaffold in the desired β-hairpin conformation, the introduction of d-proline at the i+1 turn position proved to be beneficial for both permeability and clearance. As a result, cyclopeptide decamers with unprecedented high values for oral bioavailability and exposure are reported herein. NMR spectroscopy conformation and dynamic analysis confirmed, for selected examples, the rigidity of the scaffold and the presence of transannular hydrogen bonds in polar and apolar environments. Furthermore, we showed, for one compound, that its transition from a polar environment to an apolar one was accompanied by an increased molecular motion, revealing an entropy contribution to membrane permeation.
Cyclic peptides have
received increasing attention over the recent
years as potential therapeutics for “undruggable” targets.
One major obstacle is, however, their often relatively poor bioavailability.
Here, we investigate the structure–permeability relationship
of 24 cyclic decapeptides that share the same backbone N-methylation
pattern but differ in their side chains. The peptides cover a large
range of values for passive membrane permeability as well as lipophilicity
and solubility. To rationalize the observed differences in permeability,
we extracted for each peptide the population of the membrane-permeable
conformation in water from extensive explicit-solvent molecular dynamics
simulations and used this as a metric for conformational rigidity
or “prefolding.” The insights from the simulations together
with lipophilicity measurements highlight the intricate interplay
between polarity/lipophilicity and flexibility/rigidity and the possible
compensating effects on permeability. The findings allow us to better
understand the structure–permeability relationship of cyclic
peptides and extract general guiding principles.
This study uses molecular dynamics and Markov state models to analyse how interfaces interact with cyclic decapeptides and modulate their dynamic and equilibrium properties.
We previously reported the design of several cyclic decapeptides based on a generic scaffold that achieved favorable oral bioavailability and exposure. With the goal to further investigate the potential of this approach, we describe herein the effect of mono- and difunctionalization of this scaffold. A series of cyclic decapeptides were therefore subjected to a range of in vitro assays and pharmacokinetic (PK) studies to investigate whether the introduction of polar or charged groups could be tolerated by the "engineered" scaffold while maintaining good PK profiles. Whereas the introduction of charged amino acids proved-besides maintaining low clearance-to conceal the inherent PK properties of the scaffold, the introduction of polar amino acids (i.e., threonine and pyridyl alanine) led to several cyclic decapeptides exhibiting excellent PK profiles together with a solubility that was significantly improved relative to that of previously reported cyclic decapeptides.
The total synthesis of cruentaren A, a biologically active resorcylate natural product, is reported. The aromatic unit was constructed via late-stage cyclization and aromatization from a diketodioxinone intermediate and macrocyclization using Fürstner ring-closing alkyne metathesis.
Cyclic peptides extend the druggable target space due
to their
size, flexibility, and hydrogen-bonding capacity. However, these properties
impact also their passive membrane permeability. As the “journey”
through membranes cannot be monitored experimentally, little is known
about the underlying process, which hinders rational design. Here,
we use molecular simulations to uncover how cyclic peptides permeate
a membrane. We show that side chains can act as “molecular
anchors”, establishing the first contact with the membrane
and enabling insertion. Once inside, the peptides are positioned between
headgroups and lipid tailsa unique polar/apolar interface.
Only one of two distinct orientations at this interface allows for
the formation of the permeable “closed” conformation.
In the closed conformation, the peptide crosses to the lower leaflet
via another “anchoring” and flipping mechanism. Our
findings provide atomistic insights into the permeation process of
flexible cyclic peptides and reveal design considerations for each
step of the process.
A new amide-forming ligation that requires a glycine or a primary amine at the linkage site is described herein. The distinguishing feature of this ligation is its reliance on an O-hydroxymethyl salicylaldehyde ester at the C-terminus which allows, via an N,O-acetal intermediate, the formation of a native peptide bond.
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