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  • Review Article
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Subcellular targeting strategies for drug design and delivery

Key Points

  • Although great efforts have been made to address the bioavailability and tissue targeting of drugs, little is known about drug delivery to specific subcellular compartments that harbour the drug target. As cells constantly traffic their contents to these compartments, cell biology principles could be effectively used for drug targeting.

  • For a drug to reach particular subcellular compartments, the drug has to be modified to include the appropriate signal to target it to the subcellular site, without compromising its functional moiety.

  • Protein modifications or lipid conjugations that direct a drug to targets in the plasma membrane have been shown to increase drug efficacy. These modifications reduce the dimensionality of these otherwise soluble drugs, thereby leading to an increase in effective drug concentration.

  • Cells internalize various small molecules, nutrients and pathogens and sort them to specific intracellular compartments. Drug conjugation to either the nutrient moieties or part of the pathogens that carry the targeting signal are some of the strategies used to target specific organelles.

  • In addition to membrane-bound organelles, the cytosol could also be targeted by specific modifications. Cell-penetrating peptides from viruses, viral particles, bacterial toxins, liposomes and nanoparticles are various means to target the cytosol. Targeting the cytosol is also a method for reaching the nuclear compartment.

  • Specific targeting of drugs to subcellular compartments is still in the early stages of development but shows promise. Issues such as drug stability in intracellular compartments and tissue-specific targeting are still to be addressed.

Abstract

Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to appropriate these mechanisms and the implications for drug design and delivery.

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Figure 1: Heterogeneity of internalization pathways.
Figure 2: Clathrin-mediated endocytic pathway.
Figure 3: Endosomal targeting of β-secretase inhibitors.
Figure 4: Strategies to target drugs to different cellular compartments.

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Acknowledgements

We thank M. Zerial, I. Levental, J. Ries, V. Kotelianski, C. Schroeder, Z. Maliga, G. Kalyanaraman and G. Jennings for their insightful comments on the work. We acknowledge the funding support from the Swiss National Foundation (NCCR Neuro) and a grant from Alzheimer Forschungs Initiative e.V to L.R.

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H.-J.K. and K.S. are co-founders of the biotechnology company JADO Technologies, which specializes in membrane invention technologies including lipid raft modulation.

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DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

Niemann–Pick disease type A

Niemann–Pick disease type B

Niemann–Pick disease type C

Parkinson's disease

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Target P

Nanoparticles

Glossary

Endosome

A membrane-bound vesicle that is formed by the invagination of the plasma membrane during endocytosis.

Clathrin triskelion

A clathrin structure that consists of three heavy chains and three light chains that weave together to form three 'legs' radiating from a central point. The heavy chains form the backbone whereas the light chains are involved in the formation of clathrin lattices.

Prodrug

A drug that is designed to release the active moiety only upon certain activating conditions.

Transition state inhibitor

Inhibitors that are designed to mimic the transition state of a substrate molecule in the enzyme–substrate catalytic reaction. Such inhibitors do not undergo catalysis and inhibit the enzyme at the substrate-binding site.

Bioavailability

The extent to and rate at which the drug enters the systemic circulation.

Small interfering RNA

(siRNA). Small stretches of RNA, usually 21–25 nucleotides long, that bind to mRNA and target it for degradation, thereby silencing gene expression.

Singlet oxygen

A form of molecular oxygen that is a reactive oxygen species and less stable than the normal triplet oxygen.

Blood–brain barrier

A semi-permeable cellular structure consisting of endothelial cells that allows selective passage of some molecules but prevents the passage of others.

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Rajendran, L., Knölker, HJ. & Simons, K. Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov 9, 29–42 (2010). https://doi.org/10.1038/nrd2897

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