Efficient synthesis and anticancer evaluation of spider toxin peptide LVTX-8-based analogues with enhanced stability

Chi, Qiao-Na; Jia, Shi-Xi; Yin, Hao; Wang, Lie; Fu, Xing-Yan; Ma, Yan-Nan; Sun, Ming-Pu; Qi, Yun‐Kun; Li, Zhibo; Du, Shanshan

doi:10.1016/j.bioorg.2023.106451

Cited by 11 publications

(6 citation statements)

References 60 publications

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“… As a typical oncolytic peptide, LTX-315 contains a linear amphipathic α-helical structure and a 9 amino acid residue sequence, with cationic residues (lysine) modeled on one side of the helix while the aromatic residues (tryptophan, Dip) modeled on the other side. Previous studies indicated that N-terminal acetylation and C-terminal hydrazidation may improve enzymatic stability and anticancer efficiency. − Therefore, N-terminal acetylation and C-terminal hydrazidation were first conducted on LTX-315, affording FXY-13, FXY-17, and FXY-18 (Table ). Besides, the N-terminal PEG and alkylation of LTX-315 were conducted, affording FXY-19 and FXY-20 respectively.…”

Section: Resultsmentioning

confidence: 99%

“…After all amino acid residues of LTX-315 were coupled, double coupling (first for 60 min and second for 90 min) was conducted using a solution of coupling ((2-amino)ethoxy)acetic acid (2 equiv) or 6-aminohexanoic acid (2 equiv), HATU (1.8 equiv), HOAt (2 equiv), and DIEA (4 equiv) at 28 °C. 7-(Diethylamino)-coumarin-3-carboxylic acid (7-DCCA) has been widely utilized for cell fluorescence imaging of peptides …”

Section: Methodsmentioning

confidence: 99%

“…The stability of synthetic peptides was first investigated at the human serum level. , For the human serum experiment, the synthetic peptides were dissolved in the PBS solution at a final concentration of 100 μM. 10% human serum was added to the peptide solutions, and incubated at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Hemolytic activity was performed as described previously. 67 The hemolytic activity of peptides and CPT was determined in fresh human erythrocytes. Fresh human erythrocytes were collected by centrifugation at the speed of 1000 r/min for 10 min.…”

Section: 7mentioning

confidence: 99%

“…7-(Diethylamino)-coumarin-3-carboxylic acid (7-DCCA) has been widely utilized for cell fluorescence imaging of peptides. 67 The fluorescent FXY-21 and FXY-22 were obtained by coupling 7-DCCA to LTX-315 and FXY-12. Double coupling (first for 1 h, and then 1.5 h) was conducted at 28 °C, using the mixture of 7-DCCA (4 equiv), HCTU (2 equiv), and DIEA (4 equiv).…”

Section: Synthesis Of Ltx-315-derived and Hybridized Peptidesmentioning

confidence: 99%

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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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