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Mechanism of Action of a Therapeutic Peptide, Risuteganib, Suggests that Supporting Mitochondrial Function Underlies its Clinical Efficacy in Treating Leading Causes of Blindness


Zhou, Dan (2021) Mechanism of Action of a Therapeutic Peptide, Risuteganib, Suggests that Supporting Mitochondrial Function Underlies its Clinical Efficacy in Treating Leading Causes of Blindness. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/9kqf-yr35.


Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness in the developed world and on the rise globally due to the growth of an aging population and an increasing number of diabetics. Antibodies of vascular endothelial growth factor (VEGF), which target neovascularization in the advanced stages of both diseases, have been the main treatment for the past decade. However, anti-VEGF therapies suffer from short half-life and high cost inherent to antibodies, limiting the medical availability to a broader population.

To fill the unmet medical need for treating retinal diseases, a novel therapeutic oligopeptide, risuteganib, is currently in Phase II clinical trials. Results from completed trials suggest that risuteganib has comparable drug efficacy to anti-VEGF therapies, long half-life, low cost, and absence of drug-related adverse events in several hundred patients enrolled in clinical trials for diabetic macular edema (DME) and dry AMD. Risuteganib was originally designed to target neovascularization, intending to inhibit integrin cell-surface receptors and thereby block adhesion and migration of abnormal blood vessel cells. Early in our study, we found experimental evidence contrary to this mechanism of action (MOA).

Our journey began with an unbiased search for the binding loci in retinal tissue, using peptide-directed fluorescent labeling. We found out that risuteganib specifically binds to a monolayer of cells, the retinal pigment epithelium (RPE), which has essential functions in maintaining the homeostasis of the retina, and its dysfunction is the hallmark for both blinding retinal diseases. In vitro study in an RPE cell model, ARPE19, showed that risuteganib protects cells against elevated oxidative stress that is associated with AMD and DR. This protective effect correlates with maintaining mitochondrial function. Further study of mitochondrial bioenergetics, in collaboration with Dr. Cris Kenney at UCI, revealed that risuteganib supports oxidative phosphorylation metabolism in the mitochondria.

Based on the chemical similarity of risuteganib with a natural product, we hypothesized that risuteganib may act through a mitochondrial enzyme, pyruvate dehydrogenase kinase (PDK), specifically PDK1 that is responsive to disease-related hypoxia-inducible factor 1 alpha (HIF-1α). Protein phosphorylation assay and enzymatic assay confirmed that risuteganib inhibits PDK1, as a result, reducing phosphorylation of an essential enzyme, pyruvate dehydrogenase (PDH). Leaving PDH in its unphosphorylated form allows its continued activity in oxidative phosphorylation metabolism, which offers a molecular explanation of the ability to support mitochondrial activity. This leads to our current hypothesis that risuteganib’s mechanism of action (MOA) is through inhibition of PDK and protection of mitochondrial functions in RPE cells for treating retinal diseases.

Protecting mitochondrial functions may be beneficial to other cell types and in other diseases that subject cells to oxidative stress. As the mitochondria targeting is a potential therapy for diverse life-threatening diseases, including inflammatory disease, cardiovascular disease, and cancer, the present hypothesis invites us to expand our scope of view for this study to broader applications.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Therapeutic peptide; mechanism of action; retinopathy; mitochondrial function
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Kornfield, Julia A.
Thesis Committee:
  • Shapiro, Mikhail G. (chair)
  • Clemons, William M.
  • Tirrell, David A.
  • Kornfield, Julia A.
Defense Date:14 May 2021
Non-Caltech Author Email:zhoud97 (AT)
Funding AgencyGrant Number
Allegro OphthalmicsUNSPECIFIED
Schlumberger FoundationUNSPECIFIED
Record Number:CaltechTHESIS:05282021-020006678
Persistent URL:
Related URLs:
URLURL TypeDescription ItemARVO annual meeting abstract related for Ch. 2 and 3
Zhou, Dan0000-0003-2367-2822
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14186
Deposited By: Dan Zhou
Deposited On:03 Jun 2021 15:40
Last Modified:25 Jan 2023 17:19

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