Peptidomimetics Therapeutics for Retinal Disease

Abstract

Ocular disorders originating in the retina can result in a partial or total loss of vision, making drug delivery to the retina of vital importance. However, effectively delivering drugs to the retina remains a challenge for ophthalmologists due to various anatomical and physicochemical barriers in the eye. This review introduces diverse administration routes and the accordant pharmacokinetic profiles of ocular drugs to aid in the development of safe and efficient drug delivery systems to the retina with a focus on peptidomimetics as a growing class of retinal drugs, which have great therapeutic potential and a high degree of specificity. We also discuss the pharmacokinetic profiles of small molecule drugs due to their structural similarity to small peptidomimetics. Lastly, various formulation strategies are suggested to overcome pharmacokinetic hurdles such as solubility, retention time, enzymatic degradation, tissue targeting, and membrane permeability. This knowledge can be used to help design ocular delivery platforms for peptidomimetics, not only for the treatment of various retinal diseases, but also for the selection of potential peptidomimetic drug targets.

Thrombospondin-1 proteomimetic polymers exhibit anti-angiogenic activity in a neovascular age-related macular degeneration mouse model

“…While peptides are proposed as promising alternative therapeutics due to their binding specificity and biological delivery, they suffer from severely limited half-lives, low in vivo activity due to degradation, and low binding affinities ( 45 , 46 ). Few peptidomimetic drugs have been investigated to target ocular diseases, like nAMD ( 47 ). A small cyclic retro-inverted VEGF-targeting peptide, Vasotide, was administered via eyedrops and showed substantial reduction in angiogenesis ( 19 ).…”

“…A small cyclic retro-inverted VEGF-targeting peptide, Vasotide, was administered via eyedrops and showed substantial reduction in angiogenesis ( 19 ). However, these studies lacked pharmacokinetic profiles ( 19 , 47 ). As opposed to traditional peptidomimetic strategies such as cyclization, we address these efficacy and stability challenges by using an anti-angiogenic peptide-polymer conjugate with notably enhanced affinity for its receptor and vastly improved efficacy in models of nAMD.…”

Calpains as mechanistic drivers and therapeutic targets for ocular disease

“…Small molecule peptidomimetics, designed to mimic natural protein-peptide interactions, are attractive calpain inhibitors [131]. High-throughput screening of peptidomimetic candidates combined with their structural modifications to enhance specificity and stability (e.g., replacement of natural/unnatural amino acid side chains, cyclization, and/or non-peptide small molecules) can identify lead compounds for the drug development pipeline: hit-to-lead optimization, in vitro testing, and in vivo studies.…”

An intravitreal implant injection method for sustained drug delivery into mouse eyes

“…Ocular drug implants (ODIs) are controlled release devices that can maintain ocular drug concentrations at therapeutic levels for prolonged durations. Controlled drug release over extended periods of time can greatly reduce dosing frequency, which can improve medication adherence in patients and reduce risk during procedures if the drug needs frequent intraocular injection ( Parsons et al, 2021 ). ODIs can be especially beneficial for treating slow-progressing, chronic posterior segment eye diseases, such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa.…”