Conformational studies of Ant–Pro motif-incorporated cyclic peptides: gramicidin S and avellanin

Kotmale, Amol S.; Sangtani, Ekta; Gonnade, Rajesh G.; Sarkar, Dhiman; Burade, Sachin S.; Rajamohanan, Pattuparambil R.; Sanjayan, Gangadhar J.

doi:10.1039/c7nj03701e

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…Impressively, extra amino groups on Pro often resulted in decreased hemolytic activity while largely maintaining the antimicrobial activity, leading to a popular modification strategy . In addition to the analogues presented here, there are some other similar GS analogues, including some very recently reported examples. , Nevertheless, either no biological profile improvement was observed or their design is similar to the peptides already described, and therefore, they will not be presented in detail here.…”

Section: Structure–activity Relationship Of Gramicidin S and Its Anal...mentioning

confidence: 97%

“…40 In addition to the analogues presented here, there are some other similar GS analogues, including some very recently reported examples. 57,58 Nevertheless, either no biological profile improvement was observed or their design is similar to the peptides already described, and therefore, they will not be presented in detail here. β-Strand Region Modifications.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

et al. 2019

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Gramicidin S (GS), one of the oldest commercially used peptide antibiotics, is known for its robust antibacterial activity against both Gram-positive and Gram-negative bacterial strains. Although it was discovered well over 70 years ago, its clinical potential was limited to topical applications because of its high hemolytic activity. To overcome this side effect, significant efforts have been invested in the chase for GS analogues with high therapeutic index (e.g., high antimicrobial activity and low hemolytic activity) in the past decades. In this Perspective, the structural properties and biological profiles (including the recently discovered activities) of representative GS analogues designed by different approaches are described and analyzed. We also present how the general structure–activity relationships were established and how they could help in the design of more efficient GS analogues.

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Section: Structure–activity Relationship Of Gramicidin S and Its Anal...mentioning

confidence: 97%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

et al. 2019

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“…For example, monocyclic β-amino acids can be accommodated quite comfortably within peptide macrocycles ranging in size from 4 to 10 amino acids (e.g., 110 – 113 , Figure a), and in many cases the overall molecular conformation is little changed from that of the corresponding homodetic cyclic peptide. − Such replacements can be valuable for several reasons (e.g., enhanced synthetic efficiency, potent biological activity), but because they are “conformationally conservative,” they are not the focus of this review.…”

Section: The Effect Of Structural Modification On the Conformations O...mentioning

confidence: 99%

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

2020

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Cyclic peptides are promising scaffolds for drug development, attributable in part to their increased conformational order compared to linear peptides. However, when optimizing the target-binding or pharmacokinetic properties of cyclic peptides, it is frequently necessary to “fine-tune” their conformations, e.g., by imposing greater rigidity, by subtly altering certain side chain vectors, or by adjusting the global shape of the macrocycle. This review systematically examines the various types of structural modifications that can be made to cyclic peptides in order to achieve such conformational control.

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“…[18,19] It has become clear that the biological activity of GS is determined by a panel of physicochemical parameters: cationicity, hydrophobicity, amphiphilicity and hydrophobic aromaticity. [18] In the past decades, many strategies, including ring size variation, [20][21][22] β-turn modification, [23][24][25][26][27][28][29][30] β-strand modification [31,32] and light-controllable "smart" analogues [33][34][35] have been recognized as different routes to conceive new potent antimicrobial molecules endowed with low toxicity against human cells. However, to date, there is no clinically applicable antibiotic related to GS and thus a constant investment in this field is required.…”

Section: Introductionmentioning

confidence: 99%

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ‐Diamino Acids

Guan

Chen

et al. 2020

ChemMedChem

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Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical applications due to undesired hemolytic activity. With the aim to obtain non-toxic GS analogues, we describe herein a molecular approach where the native GS β-turn region is replaced by synthetic β,γ-diamino acids (β,γ-DiAAs). Four β,γ-DiAA diastereomers were employed to mimic β-turn structure to afford GS analogues GS3-6 that exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (βR,γS)-DiAA displays the most stable β-turn mimic. To further improve the therapeutic index (e.g. high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K, GS6F and GS display comparable antibacterial activity while GS6K and GS6F possess significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of membrane. Results and DiscussionScope of Lead Peptide Molecular Design and Synthesis. Initially, four diastereomeric GS analogues (GS3-6, Figure 1) were synthesized to evaluate in both biological and conformational aspects. The β,γ-DiAAs were prepared using the synthetic strategy previously described by our group starting from α-amino acids. [42] With respect to the aromatic character in the β-turn region, [36,39] D-and L-phenylalanine were chosen as starting materials (Scheme 1). Cbz-protected intermediates 7, 8, 9 and 10 were prepared as previously described. [23,43] Since the configuration of an analogue of compound 9 has been previously determined by crystallographic structure, [43] the other compounds could thereby be differentiated by the comparison of their NMR spectrum with their enantiomers. Noteworthy, the separation of the diastereomers is rather difficult when directly applying the silica gel chromatography. Alternatively, the minor diastereomers (8 and 10) can be easily precipitated in the presence of cold diethyl ether, and it consequently allows the major diastereomers (7 and 9) being purified by chromatography. To allow the solid phase synthesis, Cbz protecting group was further transferred to Fmoc protecting group (Scheme 1).Previous studies have demonstrated that GS and its analogues can be readily synthesized by solution-phase cyclization of the corresponding linear precursor peptides with protected side chains. [44] To this end, the linear precursors were assembled by following an either conventional or microwave-assistant solid phase Fmoc/tBu strategy. All Fmoc-protected α-amino acids are commercially available. Each projected peptide was assembled stepwise on the solid support starting from Fmoc-Pro-2-Chlorotrityl Chloride (CTC) Resin. During the sequential coupling, HBTU/HOBt (conventional synthesis) or HBTU (microwave-assistant synthesis) was used for activation, DiPEA as base,...

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Conformational studies of Ant–Pro motif-incorporated cyclic peptides: gramicidin S and avellanin

Abstract: Conformational studies suggest that an AntDPro motif-incorporated synthetic gramicidin S analog retains β-sheet conformation, while its truncated analog avellanin disturbs the β-sheet conformation.

Cited by 5 publications

References 33 publications

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

Recent Advances in the Exploration of Therapeutic Analogues of Gramicidin S, an Old but Still Potent Antimicrobial Peptide

Strategies for Fine-Tuning the Conformations of Cyclic Peptides

Development of Therapeutic Gramicidin S Analogues Bearing Plastic β,γ‐Diamino Acids

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