Synthesis of Novel Fatty-Acyl Gratisin Derivatives

Tamaki, Makoto; Harada, T.; Fujinuma, Kenta; Takanashi, Kazumasa; Shindo, Mitsuno; Kimura, Masahiro; Uchida, Yoshiki

doi:10.1248/cpb.60.743

Cited by 2 publications

(4 citation statements)

References 13 publications

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“…HBS buffer and 1 % triton X-100 were used as negative and positive controls respectively. [24] (See Supporting Information Section 6.2).…”

Section: Haemolytic Activitymentioning

confidence: 99%

Smart Wearable Patches Using Light‐Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides

Kalyvas,

Facal Marina,

Stachura

et al. 2023

Chemistry A European J

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A novel strategy to treat Staphylococcus aureus (S. aureus) skin infections is presented, where UV light is used to facilitate concomitant light‐controlled activation and delivery of an antimicrobial therapeutic agent. Specifically, a new photoswitchable gramicidin S analogue was immobilized onto a polymeric wearable patch via a photocleavable linker that undergoes photolysis at the same wavelength of light required for activation of the peptide. Unlike toxic gramicidin S, the liberated active photoswitchable peptide exhibits antimicrobial activity against S. aureus while being ostensibly non‐haemolytic to red blood cells. Moreover, irradiation with visible light switches off the antimicrobial properties of the peptide within seconds, presenting an ideal strategy to regulate antibiotic activity for localized bacterial infections with the potential to mitigate resistance.

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“…HBS buffer and 1 % triton X-100 were used as negative and positive controls respectively. [24] (See Supporting Information Section 6.2).…”

Section: Haemolytic Activitymentioning

confidence: 99%

Smart Wearable Patches Using Light‐Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides

Kalyvas,

Facal Marina,

Stachura

et al. 2023

Chemistry A European J

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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%

“…Among the molecular approaches, we are particularly interested in the modification of D Phe-Pro motif in the β-turn region. Several studies have shown that even subtle changes in the β-turn region could have a dramatic impact on the biological profile, [26,27,32,36] suggesting this region is a promising target for modulating GS structure and activity. Both α-amino acids and unnatural dipeptide surrogates have been employed to substitute the native D Phe-Pro motif.…”

Section: Introductionmentioning

confidence: 99%

“…Both α-amino acids and unnatural dipeptide surrogates have been employed to substitute the native D Phe-Pro motif. [32,37,38] Interestingly, mimicking the β-turn by unnatural dipeptide surrogates often results in a slight distortion of the cyclic β-hairpin structure and subsequently leads to an optimal amphiphilicity. [26,39] In our group, we have also contributed in the development of GS-based antibiotics.…”

Section: Introductionmentioning

confidence: 99%

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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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Synthesis of Novel Fatty-Acyl Gratisin Derivatives

Cited by 2 publications

References 13 publications

Smart Wearable Patches Using Light‐Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides

Smart Wearable Patches Using Light‐Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides

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

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