Efficient Chemical Synthesis and Oxidative Folding Studies of Scorpion Toxin Peptide WaTx

Yin, Hao; Chen, Xitong; Fu, Xing-Yan; Ma, Yan-Nan; Xu, Yimei; Zhang, Te; Liang, Shuai; Du, Shanshan; Qi, Yun‐Kun; Wang, Kewei

doi:10.6023/a21120580

Cited by 9 publications

(5 citation statements)

References 38 publications

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“…The hybrid peptides were prepared using 9-fluorenylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis in a normal air-bath thermostatic oscillator [25]. In particular, DIC/Oxymabased coupling reactions at 50 °C were applied to improve the synthetic efficiency [25][26][27]. Briefly, 160 mg of Rink Amide AM resin (0.05 mmol, 1 eq, Tianjin Nankai Hecheng Technology) was swelled in a DMF/DCM = 1:1 (v/v) solution for 1 h. The Fmoc group of the resin was removed by two treatments with 20% piperidine in DMF (5 min and 10 min) at 50 °C, followed by thorough washing with DMF and DCM.…”

Section: Synthesis Of Hybrid Peptidesmentioning

confidence: 99%

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus

et al. 2022

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The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells. Thus, four hybrid peptides, NTP-212, NTP-217, NTP-223 and NTP-385, were synthesized. These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4-to 37.5-fold. In model mice bearing B16-F10 melanoma xenografts, injection of NTP-385 (0.5 mg per mouse for 3 consecutive days) induced almost complete regression of melanoma, prolonged the median survival time and increased the overall survival. Notably, the administered dose of NTP-385 was only half the effective dose of LTX-315. We further revealed that unlike LTX-315, which targets the mitochondria, NTP-385 disrupted the nuclear membrane and accumulated in the nucleus, resulting in the transfer of a substantial amount of reactive oxygen species (ROS) from the cytoplasm to the nucleus through the fragmented nuclear membrane. This ultimately led to DNA double-strand break (DSB)-mediated intrinsic apoptosis. In conclusion, this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis. This study also provides an advantageous reference for nucleus-targeting peptide modification.

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Section: Synthesis Of Hybrid Peptidesmentioning

confidence: 99%

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus

et al. 2022

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“…A robust synthetic method was established for the accelerated manual synthesis of LTX-315-derived peptides and hybrid peptides. Previous studies indicated that the DIC/Oxyma condensation system, which featured high condensation efficiency and low risk of explosion, exhibited significant potency to inhibit side reactions represented by the racemization. − Nevertheless, the DIC/Oxyma-based condensation system was mostly conducted at 70 °C or even higher temperatures, which may induce burns to operators and instrument damage. − Using our previously established DIC/Oxyma-based strategy under moderate condensation conditions, the peptides were efficiently synthesized in a normal constant-temperature shaker at 50 °C (Figure A). − Meanwhile, to attach the CPT, the CPT was first reacted with succinic anhydride, affording the CPT-COOH with the isolated yield of 73.4% and the RP-HPLC purity above 95% (Figures B, S26, and S27). The HATU/HOAt/DIEA system was applied for the condensation of N-terminal Abz, AEEA, CPT-COOH, or 7-(diethylamino)coumarin-3-carboxylic acid at 28 °C.…”

Section: Resultsmentioning

confidence: 99%

“…The chemical structures of reagents for peptide synthesis are provided in Figure S1. The N , N ′-diisopropylcarbodiimide (DIC)/ethyl 2-cyano-2-(hydroxyimino)-acetate (Oxyma)-based condensation system was applied for the efficient coupling of amino acids. , Briefly, 300 mg of Rink Amide AM resin (0.1 mmol, 1 equiv) was added into the peptide synthesis vessel. After a standard washing procedure (DMF twice, DCM twice, DMF once, DCM once, DMF twice), the resin was swollen in DMF/DCM = 3:1 (v/v) solution for 2.5 h at 28 °C.…”

Section: Methodsmentioning

confidence: 99%

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

Fu,

Yin,

Chen

et al. 2024

J. Med. Chem.

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Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated. The D-type peptides represented by FXY-12 possessed significantly improved proteolytic stability and sustained anticancer efficiency. Strikingly, the novel hybrid peptide FXY-30, containing one FXY-12 and two camptothecin moieties, exhibited the most potent in vitro and in vivo anticancer activities. The mechanism explorations indicated that FXY-30 exhibited rapid membranolytic effects and induced severe DNA double-strand breaks to trigger cell apoptosis. Collectively, this study not only established robust strategies to improve the stability and anticancer potential of oncolytic peptides but also provided valuable references for the future development of D-type peptides-based hybrid anticancer chemotherapeutics.

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“…Besides the traditional coupling reagents such as HATU and HCTU, the novel DIC/Oxyma condensation system, which could reduce racemization and other side reactions, should also be utilized for the synthesis of teixobactin. 83,[95][96][97][98] Meanwhile, the linear hexapeptide 43 was readily synthesized on 2-CTC resin through standard Fmoc SPPS (Figure 16). Through the condensation between cyclic pentapeptide 48 and linear hexapeptide 43 at Ile 6 -Ser 7 site, followed by the global removal of the protecting groups, the final teixobactin was obtained on 1.2-gram scale (31% overall isolated yield from compound 48 and 8% overall isolated yield from compound 45).…”

Section: Gram-scale Synthesis Of Teixobactin By the Rao Groupmentioning

confidence: 99%

“…Then, the cyclization occurred between D‐Thr 8 and Ala 9 , affording cyclic pentapeptide 48 in 58% yield. Besides the traditional coupling reagents such as HATU and HCTU, the novel DIC/Oxyma condensation system, which could reduce racemization and other side reactions, should also be utilized for the synthesis of teixobactin 83,95–98 …”

Section: Total Synthesis Of Teixobactinmentioning

confidence: 99%

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

Tang

Wang

et al. 2022

Journal of Peptide Science

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Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever‐increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide‐based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram‐positive pathogens and Mycobacterium tuberculosis, including drug‐resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l‐allo‐End, natural teixobactin, representative teixobactin analogs, as well as the structure–activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

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Efficient Chemical Synthesis and Oxidative Folding Studies of Scorpion Toxin Peptide WaTx

Cited by 9 publications

References 38 publications

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

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