Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration

Int J Mol Sci. 2021 Apr 9;22(8):3893. doi: 10.3390/ijms22083893.


It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.

Keywords: VEGF; VEGFR-2; acetylated tetrapeptide (Ac-RLYE); laser-induced CNV model; neovascular age-related macular degeneration; resistance; retinal neovascularization.

MeSH terms

  • Acetylation
  • Animals
  • Choroidal Neovascularization / drug therapy
  • Choroidal Neovascularization / metabolism
  • Choroidal Neovascularization / pathology
  • Disease Models, Animal
  • Disease Susceptibility
  • Fluorescein Angiography
  • Humans
  • Macular Degeneration / diagnosis
  • Macular Degeneration / drug therapy
  • Macular Degeneration / etiology*
  • Macular Degeneration / metabolism*
  • Male
  • Mice
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Promoter Regions, Genetic
  • Rabbits
  • Ranibizumab / pharmacology
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / pharmacology
  • Retina / metabolism
  • Retina / pathology
  • Retinal Neovascularization / drug therapy
  • Retinal Neovascularization / metabolism
  • Retinal Neovascularization / pathology
  • Swine
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / chemistry
  • Vascular Endothelial Growth Factor A / metabolism


  • Oligopeptides
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor
  • Ranibizumab