A comprehensive study on the effect of backbone stereochemistry of a cyclic hexapeptide on membrane permeability and microsomal stability

Hosono, Yuki; Morimoto, Jumpei; Sando, Shinsuke

doi:10.1039/d1ob02090k

“…The emergence of library‐based methods such as SICLOPPS and RaPID have revolutionised the discovery of biologically active macrocycles with high selectivity and specificity towards challenging intracellular targets such as protein‐protein interactions [35–37] . However, the physicochemical properties of the leads generated by library methods can be highly variable, especially if they contain all‐ l amino acids or polar side chains [38, 39] . In the present paper we demonstrate the application of this strategy to 18‐membered rings, an important and diverse class of peptide macrocycles [40] …”

Section: Introductionmentioning

confidence: 77%

“…[35][36][37] However, the physicochemical properties of the leads generated by library methods can be highly variable, especially if they contain all-L amino acids or polar side chains. [38,39] In the present paper we demonstrate the application of this strategy to 18-membered rings, an important and diverse class of peptide macrocycles. [40]…”

Section: Introductionmentioning

confidence: 87%

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

Saunders

¹

,

Yudin

²

2022

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Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N‐methylated amino acids and/or D‐amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings. Through stepwise substitution of amino acid residues for heterocycles, we show that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation‐property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles and these frameworks can now be applied as macrocyclic scaffolds for drug discovery.

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“…The observation that pK a,acidic is positively correlated with LTLE-specific permeability is in good agreement with the description of Austin et al [ 36 ], i.e., the increasing acidity of the APIs reduces the affinity to hepatocytes. It is also interesting to identify a positive correlation between LPLE-, B(P/T)LE-specific permeability, and the number of amide functions, which has a critical role in the composition of many classic small-molecule [ 37 ], peptide, or peptidomimetic drugs [ 38 ]. Here, it is worth emphasizing the observation of Ono et al in that free amide hydrogens as hydrogen bond donors interact with the membrane; moreover, the water–lipid membrane interface plays an important role in the development of high permeability [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

Natural Lipid Extracts as an Artificial Membrane for Drug Permeability Assay: In Vitro and In Silico Characterization

Vincze

¹

,

Dékány

²

,

Bicsak

³

et al. 2023

Pharmaceutics

0

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In vitro non-cellular permeability models such as the parallel artificial membrane permeability assay (PAMPA) are widely applied tools for early-phase drug candidate screening. In addition to the commonly used porcine brain polar lipid extract for modeling the blood–brain barrier’s permeability, the total and polar fractions of bovine heart and liver lipid extracts were investigated in the PAMPA model by measuring the permeability of 32 diverse drugs. The zeta potential of the lipid extracts and the net charge of their glycerophospholipid components were also determined. Physicochemical parameters of the 32 compounds were calculated using three independent forms of software (Marvin Sketch, RDKit, and ACD/Percepta). The relationship between the lipid-specific permeabilities and the physicochemical descriptors of the compounds was investigated using linear correlation, Spearman correlation, and PCA analysis. While the results showed only subtle differences between total and polar lipids, permeability through liver lipids highly differed from that of the heart or brain lipid-based models. Correlations between the in silico descriptors (e.g., number of amide bonds, heteroatoms, and aromatic heterocycles, accessible surface area, and H-bond acceptor–donor balance) of drug molecules and permeability values were also found, which provides support for understanding tissue-specific permeability.

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“…We decided to use 18‐membered cyclo(PGLGFA) 1 for several reasons. It is known to be difficult to achieve permeation in an all‐ l peptide backbone, [39] and 1 is known to display poor permeability (Table 1). Additionally, 1 exhibits a mixture of conformations at room temperature on the NMR timescale, offering the possibility to investigate changes in structural organisation as a result of heterocyclic grafting [41] .…”

Section: Resultsmentioning

confidence: 99%

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

Saunders

¹

,

Yudin

²

2022

View full text Add to dashboard Cite

Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N‐methylated amino acids and/or D‐amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings. Through stepwise substitution of amino acid residues for heterocycles, we show that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation‐property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles and these frameworks can now be applied as macrocyclic scaffolds for drug discovery.

show abstract

A comprehensive study on the effect of backbone stereochemistry of a cyclic hexapeptide on membrane permeability and microsomal stability

Abstract: The effect of backbone stereochemistry of a cyclic hexapeptide on membrane permeability and metabolic stability was comprehensively evaluated. Besides, the effect of side chain structures on the pharmacokinetic properties was investigated.

Cited by 9 publications

References 22 publications

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

Natural Lipid Extracts as an Artificial Membrane for Drug Permeability Assay: In Vitro and In Silico Characterization

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

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