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Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 15879

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Dr. Hongli Wu

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Guest Editor

Department of Pharmaceutical Sciences, University of North Texas Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
Interests: eyes; ocular diseases; cataracts
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vision is an essential part of life. Loss of vision can directly compromise a person’s quality of life and indirectly impact their health. People with vision loss are more likely to report depression, falls, cognitive decline, and premature death. With an increased aging population, vision impairment has become a major global public health problem. Recent breakthroughs, including the use of the artificial intraocular lens for cataracts and anti-VEGF molecules for wet age-related macular degeneration (AMD) are some impressive examples of restoring vision. However, many unmet needs remain in the field of ocular diseases, particularly for glaucoma, diabetic retinopathy, and AMD. Moreover, due to the presence of blood–ocular barriers, ocular drug delivery has always been a challenge for ophthalmologists and pharmaceutical scientists.

In this Special Issue, we invite both reviews and original research articles related to ophthalmic drug discovery. The major goal is to highlight some of the recent findings in the field, and to discuss new drug delivery technologies and possible future targets. Topics of the Special Issue include, but are not limited to, emerging drug targets; novel drug delivery systems; new drug candidates; and old drug repurposing for eye diseases. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Hongli Wu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

retinal degeneration
glaucoma
cataract
diabetic retinopathy
drug target
drug delivery
drug candidate
gene therapy
stem cells
natural products

Published Papers (9 papers)

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Research

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16 pages, 5131 KiB

Open AccessArticle

Lutein/Zeaxanthin Isomers and Quercetagetin Combination Safeguards the Retina from Photo-Oxidative Damage by Modulating Neuroplasticity Markers and the Nrf2 Pathway

by Emre Sahin, Cemal Orhan, Nurhan Sahin, Muralidhara Padigaru, Abhijeet Morde, Mohan Lal, Nanasaheb Dhavan, Fusun Erten, Ahmet Alp Bilgic, Ibrahim Hanifi Ozercan and Kazim Sahin

Pharmaceuticals 2023, 16(11), 1543; https://doi.org/10.3390/ph16111543 - 01 Nov 2023

Cited by 1 | Viewed by 1115

Abstract

Exposure to light-emitting diode (LED) light is a primary cause of retinal damage, resulting in vision loss. Several plant-derived substances, such as lutein and quercetagetin (QCG), show promise in supporting eye health. In this study, the impact of lutein/zeaxanthin (L/Z, Lutemax 2020) and QCG were evaluated individually and together in a rat model of LED-induced retinal damage. A total of 63 Wistar rats were allocated into nine groups (n = 7). For 28 days, the rats received L/Z (10 or 20 mg/kg BW), quercetin (QC, 20 mg/kg BW), QCG (10 or 20 mg/kg BW), or a mixture of different lutein and QCG dosages, after which they were exposed to LED light for 48 h. LED exposure led to a spike in serum malondialdehyde (MDA) and inflammatory cytokines, as well as an increase in retinal NF-κB, ICAM, GFAP, and MCP-1 levels (p < 0.0001 for all). It also reduced serum antioxidant enzyme activities and retinal Nrf2, HO-1, GAP43, NCAM, and outer nuclear layer (ONL) thickness (p < 0.0001 for all). However, administering L/Z and QCG, particularly a 1:1 combination of L/Z and QCG at 20 mg/kg, effectively reversed these changes. The treatment suppressed NF-κB, ICAM, GFAP, and MCP-1 while enhancing Nrf2, HO-1, GAP43, and NCAM and preventing ONL thickness reduction in LED-induced retinal damage rats. In conclusion, while LED light exposure caused retinal damage, treatment with L/Z, QC, and QCG, particularly a combined L/Z and QCG regimen, exhibited protective effects on the retina. This is possibly due to the modulation of neuroplasticity markers and nuclear transcription factors in the rats’ retinal cells. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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19 pages, 23048 KiB

Open AccessArticle

Spironolactone Eyedrop Favors Restoration of Corneal Integrity after Wound Healing in the Rat

by Daniela Rodrigues-Braz, Linxin Zhu, Emmanuelle Gélizé, Jean-Pierre Clarin, Xavier Chatagnon, Youcef Benzine, Philippe Rampignon, Agathe Thouvenin, Jean-Louis Bourges, Francine Behar-Cohen and Min Zhao

Pharmaceuticals 2023, 16(10), 1446; https://doi.org/10.3390/ph16101446 - 12 Oct 2023

Cited by 1 | Viewed by 1100

Abstract

Abnormal corneal wound healing can compromise corneal transparency and lead to visual impairment. Mineralocorticoid receptor antagonists (MRA) are promising candidates to promote corneal remodeling with anti-inflammatory properties and lack gluococorticoids-associated side effects. In this preclinical study, a new polymer-free hydroxypropyl-gamma-cyclodextrin-based eyedrop containing 0.1% spironolactone (SPL), a potent but non-water-soluble MRA, was investigated for its ocular surface tolerance and efficacy in a rat model of corneal wound healing. SPL eyedrops were stable for up to 9 months at 4 °C. The formulation was well-tolerated since no morphological changes or inflammatory reactions were observed in the rat cornea after multiple daily instillations over 7 days. SPL eyedrops accelerated rat corneal wound healing, reduced corneal edema and inflammation, enhanced epithelial integrity, and improved nerve regeneration, suggesting restoration of corneal homeostasis, while potassium canrenoate, an active and soluble metabolite of SPL, had no effect. SPL eyedrops could benefit patients with impaired corneal wound healing, including that secondary to glucocorticoid therapy. Repurposing known drugs with known excipients will expedite translation to the clinic. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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17 pages, 6869 KiB

Open AccessArticle

Therapeutic Potential of Biochanin A in Herpes Simplex Keratitis

by Nan Zhou, Deyuan Zheng, Qiao You, Taige Chen, Jiaxuan Jiang, Wenhao Shen, Di Zhang, Junpeng Liu, Deyan Chen and Kai Hu

Pharmaceuticals 2023, 16(9), 1240; https://doi.org/10.3390/ph16091240 - 01 Sep 2023

Cited by 1 | Viewed by 1213

Abstract

Herpes simplex keratitis (HSK) is a blinding eye disease that is initiated by the herpes simplex virus type 1 (HSV-1). Resistance to acyclovir (ACV) and the side effects of corticosteroid drugs have become concerning issues, so it is crucial to develop new antivirals for treating HSK. In this study, we report that biochanin A (BCA), a naturally occurring flavonoid compound, provides multifaceted protective effects with anti-viral, anti-inflammatory, anti-oxidative stress and anti-apoptotic activities to alleviate HSK. The results show that BCA significantly inhibited HSV-1 replication in vitro and further proved that BCA principally influenced the early stage of virus infection. We reveal that BCA downregulated the expression of pro-inflammatory factors triggered by HSV-1, including TNF-α, RANTES, IL-1β and IL-6. Furthermore, BCA treatment alleviated oxidative stress and apoptotic arising from HSV-1 infection. Lastly, we induced HSK in male C57BL/6 mice and treated them with either BCA or phosphate buffer solution (PBS) eye drops. We observed the ocular surface lesions; determined the virus load in the tear fluid, corneas as well as trigeminal ganglions (TGs); and detected the levels of inflammation and apoptosis in the corneas simultaneously. These results show that BCA inhibits HSV-1 and alleviates the corneal lesion degree. Our study illustrates that BCA is a promising therapeutic approach for application in treating HSK. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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11 pages, 1677 KiB

Open AccessArticle

Drug-Repurposing Strategy for Dimethyl Fumarate

by Salvatore Giunta, Agata Grazia D’Amico, Grazia Maugeri, Claudio Bucolo, Giovanni Luca Romano, Settimio Rossi, Chiara M. Eandi, Elisabetta Pricoco and Velia D’Agata

Pharmaceuticals 2023, 16(7), 974; https://doi.org/10.3390/ph16070974 - 07 Jul 2023

Cited by 1 | Viewed by 1349

Abstract

In the area of drug discovery, repurposing strategies represent an approach to discover new uses of approved drugs besides their original indications. We used this approach to investigate the effects of dimethyl fumarate (DMF), a drug approved for relapsing–remitting multiple sclerosis and psoriasis treatment, on early injury associated with diabetic retinopathy (DR). We used an in vivo streptozotocin (STZ)-induced diabetic rat model. Diabetes was induced by a single injection of STZ in rats, and after 1 week, a group of animals was treated with a daily intraperitoneal injection of DMF or a vehicle. Three weeks after diabetes induction, the retinal expression levels of key enzymes involved in DR were evaluated. In particular, the biomarkers COX-2, iNOS, and HO-1 were assessed via Western blot and immunohistochemistry analysis. Diabetic rats showed a significant retinal upregulation of COX-2 and iNOS compared to the retina of normal rats (non-diabetic), and an increase in HO-1 was also observed in the STZ group. This latter result was due to a mechanism of protection elicited by the pathological condition. DMF treatment significantly induced the retinal expression of HO-1 in STZ-induced diabetic animals with a reduction in iNOS and COX-2 retinal levels. Taken together, these results suggested that DMF might be useful to counteract the inflammatory process and the oxidative response in DR. In conclusion, we believe that DMF represents a potential candidate to treat diabetic retinopathy and warrants further in vivo and clinical evaluation. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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21 pages, 7641 KiB

Open AccessArticle

Development of Novel Small-Molecule Activators of Pyruvate Kinase Muscle Isozyme 2, PKM2, to Reduce Photoreceptor Apoptosis

by Thomas J. Wubben, Sraboni Chaudhury, Brennan T. Watch, Jeanne A. Stuckey, Eric Weh, Roshini Fernando, Moloy Goswami, Mercy Pawar, Jason C. Rech and Cagri G. Besirli

Pharmaceuticals 2023, 16(5), 705; https://doi.org/10.3390/ph16050705 - 06 May 2023

Cited by 2 | Viewed by 1896

Abstract

Treatment options are lacking to prevent photoreceptor death and subsequent vision loss. Previously, we demonstrated that reprogramming metabolism via the pharmacologic activation of PKM2 is a novel photoreceptor neuroprotective strategy. However, the features of the tool compound used in those studies, ML-265, preclude its advancement as an intraocular, clinical candidate. This study sought to develop the next generation of small-molecule PKM2 activators, aimed specifically for delivery into the eye. Compounds were developed that replaced the thienopyrrolopyridazinone core of ML-265 and modified the aniline and methyl sulfoxide functional groups. Compound 2 demonstrated that structural changes to the ML-265 scaffold are tolerated from a potency and efficacy standpoint, allow for a similar binding mode to the target, and circumvent apoptosis in models of outer retinal stress. To overcome the low solubility and problematic functional groups of ML-265, compound 2’s efficacious and versatile core structure for the incorporation of diverse functional groups was then utilized to develop novel PKM2 activators with improved solubility, lack of structural alerts, and retained potency. No other molecules are in the pharmaceutical pipeline for the metabolic reprogramming of photoreceptors. Thus, this study is the first to cultivate the next generation of novel, structurally diverse, small-molecule PKM2 activators for delivery into the eye. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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12 pages, 2031 KiB

Open AccessArticle

Meldonium Inhibits Cell Motility and Wound-Healing in Trabecular Meshwork Cells and Scleral Fibroblasts: Possible Applications in Glaucoma

by Cristina Minnelli, Francesco Piva, Monia Cecati, Tatiana Armeni, Giovanna Mobbili, Roberta Galeazzi, Alberto Melecchi, Martina Cristaldi, Roberta Corsaro and Dario Rusciano

Pharmaceuticals 2023, 16(4), 594; https://doi.org/10.3390/ph16040594 - 15 Apr 2023

Cited by 1 | Viewed by 1718

Abstract

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine—a main player in mitochondrial energy generation—thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension. By stimulating the endothelial nitric oxide synthetase (eNOS) via PI3 and Akt kinase, it has shown beneficial effects on the microcirculation and blood perfusion. Elevated intraocular pressure (IOP) and endothelial dysfunction are major risk factors for glaucoma development and progression, and IOP remains the main target for its pharmacological treatment. IOP is maintained through the filtration efficiency of the trabecular meshwork (TM), a porous tissue derived from the neuroectoderm. Therefore, given the effects of MID on blood vessels and endothelial cells, we investigated the effects of the topical instillation of MID eye drops on the IOP of normotensive rats and on the cell metabolism and motility of human TM cells in vitro. Results show a significant dose-dependent decrease in the IOP upon topic treatment and a decrease in TM cell motility in the wound-healing assay, correlating with an enhanced expression of vinculin localized in focal adhesion plaques. Motility inhibition was also evident on scleral fibroblasts in vitro. These results may encourage a further exploration of MID eye drops in glaucoma treatment. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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12 pages, 1914 KiB

Open AccessArticle

The Structural Characteristics of Compounds Interacting with the Amantadine-Sensitive Drug Transport System at the Inner Blood–Retinal Barrier

by Yusuke Shinozaki, Yuma Tega, Shin-ichi Akanuma and Ken-ichi Hosoya

Pharmaceuticals 2023, 16(3), 435; https://doi.org/10.3390/ph16030435 - 13 Mar 2023

Viewed by 1714

Abstract

Blood-to-retina transport across the inner blood–retinal barrier (BRB) is a key determinant of retinal drug concentration and pharmacological effect. Recently, we reported on the amantadine-sensitive drug transport system, which is different from well-characterized transporters, at the inner BRB. Since amantadine and its derivatives exhibit neuroprotective effects, it is expected that a detailed understanding of this transport system would lead to the efficient retinal delivery of these potential neuroprotective agents for the treatment of retinal diseases. The objective of this study was to characterize the structural features of compounds for the amantadine-sensitive transport system. Inhibition analysis conducted on a rat inner BRB model cell line indicated that the transport system strongly interacts with lipophilic amines, especially primary amines. In addition, lipophilic primary amines that have polar groups, such as hydroxy and carboxy groups, did not inhibit the amantadine transport system. Furthermore, certain types of primary amines with an adamantane skeleton or linear alkyl chain exhibited a competitive inhibition of amantadine uptake, suggesting that these compounds are potential substrates for the amantadine-sensitive drug transport system at the inner BRB. These results are helpful for producing the appropriate drug design to improve the blood-to-retina delivery of neuroprotective drugs. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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11 pages, 994 KiB

Open AccessArticle

Evaluation of Safety, Tolerability and Pharmacokinetic Characteristics of SA001 and Its Active Metabolite Rebamipide after Single and Multiple Oral Administration

by Sungyeun Bae, Ki Young Huh, Jaeseong Oh, Kyung-Sang Yu and Anhye Kim

Pharmaceuticals 2023, 16(1), 132; https://doi.org/10.3390/ph16010132 - 16 Jan 2023

Viewed by 2615

Abstract

Dry eye disease (DED) is one of the most common eye diseases caused by multiple factors. Rebamipide, which is currently used to treat peptic ulcer disease, was shown to enhance secretory function and modulate inflammation in animal disease models. Considering the pathophysiology of DED, SA001 was developed expecting enhanced systemic exposure of rebamipide. Clinical trials to evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of SA001 and its active metabolite rebamipide were conducted. After oral administration of SA001, blood and urine samples were collected for PK analysis of SA001 and rebamipide. PK parameters were compared between SA001 and conventional rebamipide (Bamedin^®) and also between fasted and fed. Safety and tolerability were evaluated throughout the study based on adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiography and clinical laboratory tests. SA001 was rapidly absorbed and quickly converted to rebamipide. The systemic exposure of rebamipide was dose-proportional after single and multiple doses. The plasma concentration of rebamipide after administration of SA001 was higher with a dose adjusted AUC_last and C_max 2.20 and 5.45 times higher in the 240 mg dose group and 4.73 and 11.94 times higher in the 600 mg dose group compared to conventional rebamipide. The favorable PK and tolerability profiles support further clinical development. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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Review

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20 pages, 3857 KiB

Open AccessReview

Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies

by Najam A. Sharif

Pharmaceuticals 2023, 16(6), 870; https://doi.org/10.3390/ph16060870 - 12 Jun 2023

Cited by 1 | Viewed by 2288

Abstract

This review article focuses on the pathogenesis of and genetic defects linked with chronic ocular hypertension (cOHT) and glaucoma. The latter ocular disease constitutes a group of ocular degenerative diseases whose hallmark features are damage to the optic nerve, apoptotic demise of retinal ganglion cells, disturbances within the brain regions involved in visual perception and considerable visual impairment that can lead to blindness. Even though a number of pharmaceuticals, surgical and device-based treatments already exist addressing cOHT associated with the most prevalent of the glaucoma types, primary open-angle glaucoma (POAG), they can be improved upon in terms of superior efficacy with reduced side-effects and with longer duration of activity. The linkage of disease pathology to certain genes via genome-wide associated studies are illuminating new approaches to finding novel treatment options for the aforementioned ocular disorders. Gene replacement, gene editing via CRISPR-Cas9, and the use of optogenetic technologies may replace traditional drug-based therapies and/or they may augment existing therapeutics for the treatment of cOHT and POAG in the future. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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