Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma

Oncotarget. 2017 Jan 3;8(1):757-768. doi: 10.18632/oncotarget.12748.


The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin αvβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the αvβ3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of γH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the αvβ3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma.

Keywords: Integrin αvβ3; conjugate; human metastatic melanoma; non-RGD; targeted drug delivery.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • Disease Models, Animal
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Humans
  • Integrin alphaVbeta3 / chemistry
  • Integrin alphaVbeta3 / metabolism
  • Melanoma / drug therapy
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Peptides, Cyclic / therapeutic use*
  • Protein Binding
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Integrin alphaVbeta3
  • Oligopeptides
  • Peptides, Cyclic
  • arginyl-glycyl-aspartic acid
  • Caspase 3