June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Harnessing structural data to design novel ocular surface drugs
Author Affiliations & Notes
  • Tarsis G Ferreira
    Vision Sciences, University of Houston, Houston, Texas, United States
  • Fernando Ogata
    Vision Sciences, University of Houston, Houston, Texas, United States
  • Cassio Prinholato da Silva
    Vision Sciences, University of Houston, Houston, Texas, United States
  • Sudhir Verma
    Vision Sciences, University of Houston, Houston, Texas, United States
  • Vivien Jane Coulson-Thomas
    Vision Sciences, University of Houston, Houston, Texas, United States
  • Footnotes
    Commercial Relationships   Tarsis Ferreira None; Fernando Ogata None; Cassio da Silva None; Sudhir Verma None; Vivien Coulson-Thomas None
  • Footnotes
    Support  UH DOR Startup
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1884. doi:
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      Tarsis G Ferreira, Fernando Ogata, Cassio Prinholato da Silva, Sudhir Verma, Vivien Jane Coulson-Thomas; Harnessing structural data to design novel ocular surface drugs. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1884.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The cornea is continuously vulnerable to various external insults, and severe injuries leading to exacerbated inflammation and scar tissue formation causing corneal opacity and impaired vision. Currently, there are limited options available in the clinic for preventing corneal inflammation, corneal scarring, and promoting regeneration. Small hyperstable protein binders have recently emerged with great pharmaceutical potential. In order to meet the current unmet need for novel drugs that can promote corneal regeneration, while limiting scarring and suppressing inflammation, we have developed various new hyperstable protein binders for treating various corneal injuries.

Methods : We have established a platform using Monte Carlo Sampling coupled with accelerated Molecular Dynamics to identify novel drug candidates. Herein, a two-stage binder design approach was taken to search for billions of docked conformations of mini-protein scaffolds onto selected regions of target proteins, selecting favorable interacting amino acids. Peptides were then designed to maximize interactions with the target. To enhance peptide stability and increase biocompatibility, multiple variations of hydrocarbon stapling were introduced. The ability of the newly designed drugs to promote corneal wound healing was verified in vitro using a scratch assay and in vivo using debridement wounds and alkali burn models.

Results : Novel hyperstable peptides were designed targeting EGFR and TGFBRI signaling for promoting corneal wound healing. The designed peptides bind to their targets with higher affinity than the natural ligands, in micromolar and nanomolar ranges. For EGFR, we were able to design antagonists for Cbl-c, a ubiquitin ligase that is present in keratocytes and responsible for EGFR uquiquitination/degradation. Our novel drugs prevented EGFR degradation consequently increasing EGF signaling and promoting corneal epithelial cell proliferation and migration. For TGFBRI, hyperstable peptides derived from extracellular matrix proteins were designed that promote epithelial cell migration and decrease corneal scarring.

Conclusions : We have successfully designed a set of hyperstable peptide binders that significantly promote corneal wound healing in vivo. Our established platform has the potential to identify and generate novel drug targets for treating a plethora of corneal diseases.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Miniproteins designed to bind Cbl-c.

Miniproteins designed to bind Cbl-c.

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