Scholarlink

Purpose <p>Post-translational methionine oxidation (MetO) modulates peptide stability and signaling in colorectal cancer (CRC), influencing tumor progression and therapy response. This study aimed to develop a proteomics- and computational-guided framework to identify oxidation-filtered, stage-specific plasma peptide fragments (SPFs) with physicochemical stability, proteolytic resistance, and cell-penetrating potential, and to evaluate their suitability as peptide–drug conjugate (PDC) candidate in CRC.</p> Methods <p>Stage-specific plasma proteomics (ESI–nanoLC–MS/MS) identified 8,912 peptides across early (ESCRC) and advanced (ASCRC) CRC. MetO-based filtering and Venn selection yielded candidate SPFs evaluated using ProtParam (stability), PeptideCutter (protease susceptibility), and CellPPD (cell-penetrating motifs). Molecular docking (SeamDock) was performed with CRC chemotherapeutics, and PepATTRACT was used to assess peptide–protein interactions with target enzymes.</p> Results <p>Twenty-nine SPFs showed stage specificity and MetO enrichment; six were stable by ProtParam. An ORM2-derived peptide (SDVMYTDWK) displayed high stability (instability index 19.83; aliphatic index 73.12) and strong binding affinity with irinotecan (− 6.8&#xa0;kcal/mol). CellPPD predicted moderate CPP potential with amphipathicity (~ 1.1), mild cationicity (+ 1), and near-neutral hydrophobicity (− 0.37 to − 0.42). PepATTRACT modeling revealed ORM2 interaction with DNA topoisomerase I (Top1) near the catalytic pocket, supporting its role as a targeted PDC candidate for irinotecan delivery.</p> Conclusion <p>This integrative proteomic–computational workflow identifies ORM2 as a naturally stable, moderately cell-penetrating peptide capable of selective drug delivery. The findings highlight a cost-effective strategy for rational PDC design and demonstrate ORM2’s translational potential for targeted chemotherapy in early-onset and drug-resistant CRC.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Proteomics-Guided Discovery and Computational Validation of Stable, Cell-Penetrating Plasma Peptides for Targeted Drug Delivery in Colorectal Cancer

  • 期刊论文

  • 发表日期：

    2026年1月13日

查看全文
  • Raajesh Anand Natarajan,
  • Siva Kaliyamoorthy,
  • Vinoth Boopathy,
  • Jawahar Ramasamy,
  • Ravikumar Sambandam

摘要

Purpose

Post-translational methionine oxidation (MetO) modulates peptide stability and signaling in colorectal cancer (CRC), influencing tumor progression and therapy response. This study aimed to develop a proteomics- and computational-guided framework to identify oxidation-filtered, stage-specific plasma peptide fragments (SPFs) with physicochemical stability, proteolytic resistance, and cell-penetrating potential, and to evaluate their suitability as peptide–drug conjugate (PDC) candidate in CRC.

Methods

Stage-specific plasma proteomics (ESI–nanoLC–MS/MS) identified 8,912 peptides across early (ESCRC) and advanced (ASCRC) CRC. MetO-based filtering and Venn selection yielded candidate SPFs evaluated using ProtParam (stability), PeptideCutter (protease susceptibility), and CellPPD (cell-penetrating motifs). Molecular docking (SeamDock) was performed with CRC chemotherapeutics, and PepATTRACT was used to assess peptide–protein interactions with target enzymes.

Results

Twenty-nine SPFs showed stage specificity and MetO enrichment; six were stable by ProtParam. An ORM2-derived peptide (SDVMYTDWK) displayed high stability (instability index 19.83; aliphatic index 73.12) and strong binding affinity with irinotecan (− 6.8 kcal/mol). CellPPD predicted moderate CPP potential with amphipathicity (~ 1.1), mild cationicity (+ 1), and near-neutral hydrophobicity (− 0.37 to − 0.42). PepATTRACT modeling revealed ORM2 interaction with DNA topoisomerase I (Top1) near the catalytic pocket, supporting its role as a targeted PDC candidate for irinotecan delivery.

Conclusion

This integrative proteomic–computational workflow identifies ORM2 as a naturally stable, moderately cell-penetrating peptide capable of selective drug delivery. The findings highlight a cost-effective strategy for rational PDC design and demonstrate ORM2’s translational potential for targeted chemotherapy in early-onset and drug-resistant CRC.

Graphical Abstract