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.
Highlights
The aggravation of population aging trend has led to an increasing prevalence of neurodegenerative diseases, in particular of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have brought heavy burdens to society and economy [1]
Thereinto, prodrug strategy seems to be a desirable approach without changing the structure and activity of parent drug
With the advance of understanding in transmembrane transport mechanisms of Carrier-mediated prodrug (CMP) and the involved transporters, which are highly expressed at the blood-brain barrier (BBB) (Table 1), it is practicable to design the carriers of CMP by referencing the endogenous substrates of these transporters
Summary
The aggravation of population aging trend has led to an increasing prevalence of neurodegenerative diseases, in particular of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have brought heavy burdens to society and economy [1]. Due to the existence of blood-brain barrier (BBB), practically 100% macromolecular and over 98% small-molecular drugs cannot enter the brain effectively, leading to most of the current available remedies far from impressive, and are unable to halt or delay the pathological processes [2]. BBB, the tightest physiologic barrier consisting mainly of endothelial cells linked by tight and adherens junctions, separates the blood circulation system from the central nervous system (CNS) [3]. A limited number of substances, e.g., most of lipophilic compounds with molecular weights < 400 ~ 500 Da, can cross the BBB via simple diffusion to reach efficacious concentrations in brain [4]. BBB plays a key role in maintaining brain homeostasis, but when facing pathological state, it strictly limits the entrance of therapeutic drugs into the brain. The search for novel brain-targeting methods still remains an ongoing concern
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