Cysteine Donor-Based Brain-Targeting Prodrug: Opportunities and Challenges

Abstract

Overcoming blood-brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for delivering agents with low-level BBB permeability into the brain. The well-known antioxidant capacities of cysteine (Cys) and its vital role in glutathione (GSH) synthesis indicate that Cys-based prodrug could potentiate therapeutic drugs against oxidative stress-related neurodegenerative disorders. Moreover, prodrug with Cys moiety could be recognized by the excitatory amino acid transporter 3 (EAAT3) that is highly expressed at the BBB and transports drug into the brain. In this review, we summarized the strategies of crossing BBB, properties of EAAT3 and its natural substrates, Cys and its donors, and Cys donor-based brain-targeting prodrugs by referring to recent investigations. Moreover, the challenges that we are faced with and future research orientations were also addressed and proposed. It is hoped that present review will provide evidence for the pursuit of novel Cys donor-based brain-targeting prodrug.

Iron homeostasis imbalance and ferroptosis in brain diseases

“…However, due to the isolation of BBB and the omnipresent γ‐glutamyl transpeptidase, which is responsible for GSH cleavage, GSH supplementation in vitro fails to achieve the ideal effect in neurological protection 253,254 . It was reported in recent years that some stable GSH analogs, prodrugs, and GSH‐coupled nanocarriers, such as ψ‐GSH, l‐cysteine, and γ‐glutamylcysteine, can overcome the disadvantages of GSH administration to achieve the aim of elevating GSH levels in the brain 249,255–259 . Therefore, drug development in GSH remains to be explored and will focus on the delivery and functional properties of drugs.…”

“…253,254 It was reported in recent years that some stable GSH analogs, prodrugs, and GSH-coupled nanocarriers, such as ψ-GSH, l-cysteine, and γ-glutamylcysteine, can overcome the disadvantages of GSH administration to achieve the aim of elevating GSH levels in the brain. 249,[255][256][257][258][259] Therefore, drug development in GSH remains to be explored and will focus on the delivery and functional properties of drugs. In addition, although GPX4 plays the central part in ferroptosis inhibition, researchers have found four other systems capable of suppressing ferroptosis act independently of GPX4 in the past few years, including ferroptosis suppressor protein 1 (FSP1)/CoQ10 pathway, GTP cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4) pathway, dihydroorotate dehydrogenase (DHODH) /CoQ Pathway, and p62/Keap1/Nrf2 Pathway.…”

Dietary Protective Potential of Fucoxanthin as an Active Food Component on Neurological Disorders

“…Lactoferrin has been shown to act as an effective brain-targeting ligand, crossing the BBB under the endocytosis of brain capillary endothelial cells; a delivery system with lactoferrin and drug coupling may have a higher likelihood of crossing the BBB. Cysteine is a precursor for the synthesis of glutathione, and drugs based on cysteine donors are recognized by excitatory amino acid transporter 3 (EAAT3) in the blood–brain region and transported to the brain . The carrier surface has been modified to form conjugated nanoparticles; the receptors N -methyl- d -aspartic (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) at the BBB junction are transmitted to the brain, which provides an idea for the modification of fucoxanthin-containing nanocarriers (Figure C).…”

“…Cysteine is a precursor for the synthesis of glutathione, and drugs based on cysteine donors are recognized by excitatory amino acid transporter 3 (EAAT3) in the blood−brain region and transported to the brain. 141 The carrier surface has been modified to form conjugated nanoparticles; the receptors N-methyl-D-aspartic (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) at the BBB junction are transmitted to the brain, 142 which provides an idea for the modification of fucoxanthin-containing nanocarriers (Figure 7C). In addition, research on extracellular vesicles (EVs) as therapeutic vehicles for targeted delivery of CNS drugs has received extensive attention.…”

Ultrasound-Assisted Enzymatic Extraction of Polysaccharides from Waste Corn Bract: Process Optimization, Characterization, Antioxidant and Anti-Diabetic Potentials

“…Oxidative stress is mainly induced by the excessive generation of Reactive Oxygen Species (ROS), which can automatically oxidize proteins, lipids, and DNA to cause a series of chronic diseases (Ni et al, 2022;Zhang et al, 2021). Increasing evidence has highlighted the role of oxidative stress in deteriorating diabetes.…”