Blood–Brain Barrier

Peterson, Darryl R.

doi:10.1002/9780470015902.a0000023.pub3

Screening for Anti‐cancer Drugs in Drosophila

Richardson

¹

,

Willoughby

²

,

Humbert

³

2015

Encyclopedia of Life Sciences

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The vinegar fly, Drosophila melanogaster, has been a cornerstone of genetic analysis and cell and developmental biology research for over 100 years. Within the last decade, Drosophila is making its mark in translational research in its utilisation in modelling human diseases and in screens for small molecule inhibitors. In particular, its use in modelling cancer development and in identifying anti‐cancer therapeutics is beginning to make an important contribution to the current drug discovery pipeline, which to date has been only poorly successful in delivering drugs, identified in vitro, into the clinic for anti‐cancer therapy. The primary advantages of the Drosophila system for use in anti‐cancer drug screening are the conservation of cancer genes/pathways between flies and mammals, its suitability for rapid phenotypic screening of chemicals for anti‐cancer effects in vivo in a high‐throughput and cost‐effective manner and its use in identifying drugs that can specifically target tumours in vivo . Key Concepts The current drug screening pipeline has been only poorly efficient in progressing anti‐cancer drugs to the clinic because of differences between in vitro and in vivo systems Drosophila melanogaster is an excellent model organism for cost‐effective high‐throughput in vivo screening for anti‐cancer compounds relevant to human cancer Drosophila larvae or adults can be readily screened in a high‐throughput manner for the effect of orally administered compounds on a particular phenotype using phenotypic or fluorescent read‐outs Drosophila models of cancer used for chemical screens include those generated by expression of cancer‐causing genes, whole animal synthetic lethality with radiation and specific cancer phenotypes Biological and technical limitations of Drosophila might restrict the discovery of compounds and their translation into the clinic Screening of orally administered drugs in flies has already proven to be successful in identifying new compounds or FDA‐approved compounds for use in cancer therapy

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Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

Zhou

¹

,

Smith

²

,

Liu

³

2021

WIREs Nanomed Nanobiotechnol

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Nearly one in six people worldwide suffer from disorders of the central nervous system (CNS). There is an urgent need for effective strategies to improve the success rates in CNS drug discovery and development. The lack of effective technologies for delivering drugs and genes to the brain due to the blood–brain barrier (BBB), a structural barrier that effectively blocks most neurotherapeutic agents from reaching the brain, has posed a formidable hurdle for CNS drug development. Brain‐homing and brain‐penetrating molecular transport vectors, such as brain permeable peptides or BBB shuttle peptides, have shown promise in overcoming the BBB and ferrying the drug molecules to the brain. The BBB shuttle peptides are discovered by phage display technology or derived from natural neurotropic proteins or certain viruses and harness the receptor‐mediated transcytosis molecular machinery for crossing the BBB. Brain permeable peptide–drug conjugates (PDCs), composed of BBB shuttle peptides, linkers, and drug molecules, have emerged as a promising CNS drug delivery system by taking advantage of the endogenous transcytosis mechanism and tricking the brain into allowing these bioactive molecules to pass the BBB. Here, we examine the latest development of brain‐penetrating peptide shuttles and brain‐permeable PDCs as molecular vectors to deliver small molecule drug payloads across the BBB to reach brain parenchyma. Emerging knowledge of the contribution of the peptides and their specific receptors expressed on the brain endothelial cells, choice of drug payloads, the design of PDCs, brain entry mechanisms, and delivery efficiency to the brain are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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