A Comprehensive Study on the Effect of Backbone Stereochemistry of a Cyclic Hexapeptide on Membrane Permeability and Microsomal Stability

Author(s):  
Yuki Hosono ◽  
Jumpei Morimoto ◽  
Shinsuke Sando

Backbone stereochemistry of cyclic peptides has been reported to have a great influence on microsomal stability and membrane permeability, two important factors that determine oral bioavailability. Here, we comprehensively investigated...

2022 ◽  
Author(s):  
Jaru Taechalertpaisarn ◽  
Satoshi Ono ◽  
Okimasa Okada ◽  
Timothy C. Johnstone ◽  
R. Scott Lokey

Despite the notoriously poor membrane permeability of peptides in general, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of “undruggable” intracellular targets. A major impediment to designing cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. Strategies for mitigating the deleterious effect of the backbone NH group on permeability include N-methylation, steric occlusion, and the formation of intramolecular hydrogen bonds with backbone carbonyl oxygens, while there have been relatively few studies on the use of polar side chains to sequester backbone NH groups. We investigated the ability of N,N-pyrrolidinyl glutamine (Pye), whose side chain contains a powerful hydrogen bond accepting C=O amide group but no hydrogen bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses of partition coefficients, lipophilic permeability efficiencies (LPE), artificial and cell-based permeability assays revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Introduction of the Pye residue thus offers a complementary tool, alongside traditional approaches, for improving membrane permeability and solubility in cyclic peptides.


Biopolymers ◽  
1978 ◽  
Vol 17 (11) ◽  
pp. 2747-2751 ◽  
Author(s):  
Chien-Hua Niu ◽  
Vincent Madison ◽  
Lila G. Pease ◽  
Elkan R. Blout

Author(s):  
Holikova Natalia

Background. One of the main issues of linguistics of the XX – early XXI century is a comprehensive study of the concept of discourse, which reflects a variety of real manifestations of human language communication in certain social spheres of its communicative space. The actualization of this concept in various scientific fields, the representatives of which study the essence and mechanisms of interaction of constants of such linguistic and philosophical dichotomies as “language and society”, “language and man”, has led to the need for its clear definition and typology of discourses etc. Despite the fact that linguists use a number of methods of discursive analysis of linguistic units, there is currently no single approach to their study within the theory of discourse.The purpose of the article is to identify and substantiate the features of the literary text in terms of modern discourse. The main objectives of the article: to determine the typological and categorical features of artistic discourse, to establish and describe the most important aspects of the study of artistic texts of different genres within discourse.Methods. The paper uses general scientific methods of observation, analysis, synthesis, comparison; linguistic methods, including the descriptive method – to interpret the discursive status of the literary text; the method of integrative analysis, which is the basis of a comprehensive study of a set of different aspects used in the study of the literary text as the embodiment of individualauthorial communicative intentions; the contextual-interpretive method – to identify probable reading strategies of reception of the literary text and its components.Results. The concept of discourse in the broadest sense is associated with all manifestations of communication. Discourse is a consequence of modeling knowledge structures that provide strategic planning, flow and control of communication, the operation of mechanisms of communicative competence, regulation of interactivity processes and more. An important communicative-semantic segment of the holistic nature of the analyzed concept is its interaction with various factors that reflect the essence of communication, in particular with the concept of the text. The linguistic tradition still has a great influence on the development of theoretical principles of categorization and typology of the concept of discourse, because until recently the discourse was often identified with the text as a complex linguistic sign that arises as a result of the process of language formation. Currently, researchers outline the structural and semantic parameters of the text with a number of features that also appear relevant and objective for the discourse: completeness; coherence; integrity; lexical, grammatical, logical, stylistic, semantic coherence; compositional completeness; communicative and pragmatic orientation, etc. Differentiation of discourses is one of the most important issues of modern discourse, which is currently a problem that researchers, based on a wide range of different socio-linguistic manifestations of communication, solve differently. To establish a typology of discourses, as well as texts, it is necessary to develop common criteria for their classification and determine the main categories of text and discourse. Artistic discourse, in contrast to other discourses, involves indirect communication of the author (sender) with numerous readers (addressees). When creating a text, the writer predicts the expected reaction to its content from readers, instead of “translating” the literary text into the discourse, the recipients carry out in their own way, based on their own knowledge, experience, feelings and emotions. The interaction of the addressee author with numerous addressees is devoid of real communicative factors, in particular temporal and local fixation. Despite the lack of direct contact, the writer's communicative influence on readers is obviously effective: if the artist has a deep knowledge of the language, individualizes and emphasizes linguistic means, it evokes a certain attitude to his literary texts and their evaluation by readers.Discussion. At the present stage of development of texts of any styles and genres requires discursive analysis, because in the language of fiction recorded authorial intentions that should “decipher” speakers in the process of dynamic cognition of semantic and semantic depths of a text, involving their own practical experience and knowledge during its decoding. We see prospects for further research of this topical problem in the study of features of artistic discourses of classic writers and famous contemporary artists, whose language creation is organically connected with the development of the Ukrainian literary word as an important component of the linguistic and cultural universe.


2020 ◽  
Vol 73 (4) ◽  
pp. 344 ◽  
Author(s):  
Daniel S. Nielsen ◽  
Rink-Jan Lohman ◽  
Huy N. Hoang ◽  
David P. Fairlie ◽  
Timothy A. Hill

The cyclic heptapeptide derivative, sanguinamide A, is a model scaffold for studying how component amino acids, heterocycles, and N-methylation influence membrane permeability and oral bioavailability. Membrane permeable sanguinamide A analogues have been reported, but there is limited data on their pharmacokinetic properties invivo. Here we report pharmacokinetic properties for highly cell and membrane permeable sanguinamide A analogues in rats and find that there is no correlation between reported permeability invitro and oral bioavailability invivo. We show that N-methylation of sanguinamide A analogues gives compounds with greater flexibility, greater susceptibility to degradation by rat liver microsomes, and lower oral bioavailability in rats.


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