Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery
Abstract
:1. Introduction
2. Intracellular Trafficking Processes
3. Oligonucleotide Release from Endosomes
4. Influencing Oligonucleotide Actions by Manipulation of the Endosomal Trafficking Machinery
5. Manipulation of Oligonucleotide Delivery and Effect Using Small Molecules
6. Possible Chemical Interventions in Oligonucleotide Trafficking
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Identify of Component | Function in Trafficking | Reference |
---|---|---|
Adaptor and coat proteins | Involved in initial pinching off of membrane vesicles. A well-known example is the clathrin/dynamin system. | [16] |
Tethering proteins | Provide recognition between two membrane compartments. An example are the Golgins that direct vesicles to distinct Golgi sub-compartments. | [17,18] |
SNARES/NSF-SNAP | Fusion of intracellular membranes is mediated by SNARE proteins while re-segregation of SNARES is mediated by the NSF/SNAP complex. | [19,20] |
ESCRT Complex | A multi-protein complex that is responsible for the generation of the ILVs that populate MVBs. This complex also plays a role in several other cellular functions. | [13,21] |
Retromer complex | A multi-protein complex that forms vesicles that shuttle between early endosomes and the trans-Golgi. | [12,22,23] |
Rab proteins | Members of this large family of GTPases direct many aspects of intracellular trafficking. | [24,25] |
Lipids: lysobisphosphatidic acid, certain phosphatidyl inositides | These lipids are preferentially found in MVBs/LEs. | [26] |
Endo- Membrane Target | Small Molecule | Mechanism of Action | Reference |
---|---|---|---|
GOLGI | |||
Secramine | A CDC42 inhibitor that affects export from the Golgi. Likely multiple effects on cytoskeleton. | [73] | |
YM201636 | A PI-3P-5-kinase inhibitor that blocks endosome to trans-Golgi traffic, possibly endosome to lysosome traffic, and is a modulator of autophagy. | [74,75] | |
A5, others | Small molecule inhibitors of traffic between the trans-Golgi and endosomes. | [76] | |
CI-976 | A lysophospholipid acyltransferases inhibitor that blocks a late step in COPII vesicle formation in Golgi. | [77] | |
Brefeldins | Inhibit the GEFS of Arf GTPases resulting in Golgi disassembly. | [78,79] | |
LE/MVBs | |||
Vacuolins | Induce the formation of large, swollen structures derived from endosomes and lysosomes; vacuolins are thought to be inhibitors of PI-3P-5-kinase. | [80,81,82] | |
Ceramide | Promotes budding of intraluminal vesicles. | [83] | |
Retromer | |||
Retro compounds | Block toxin trafficking, increase effects of oligonucleotides; mechanism involves inhibition of endoplasmic reticulum exit site component Sec16A. | [63,64,65,66] | |
RABs | |||
ABMA DABMA | Adamantane like compounds reduce expression of Rab7a and delay intracellular trafficking of endosomal contents. | [84] | |
CID 1067700 | Partially selective inhibitor of Rab 7. | [85] | |
Peptide inhibitor | Rab 8a inhibitor. | [86] | |
Statins | Inhibit Rab associations with Endosomes. | [87] |
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Juliano, R.L. Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery. Biomedicines 2021, 9, 512. https://doi.org/10.3390/biomedicines9050512
Juliano RL. Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery. Biomedicines. 2021; 9(5):512. https://doi.org/10.3390/biomedicines9050512
Chicago/Turabian StyleJuliano, Rudolph L. 2021. "Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery" Biomedicines 9, no. 5: 512. https://doi.org/10.3390/biomedicines9050512