Extracellular Vesicles (EVs): See also Drug delivery using exosomes
Mammalian cells normally secrete two types of EVs, smaller vesicles of about 30-200 nm that are commonly referred to as exosomes, and larger vesciels (typically >300 m) that are commonly referred to as microvesciels. (Gould, “Exosome-medaited mRNA delivery in vivo is safe adn can be used to induce SARS-CoV-2 immunity” J. Biiological Chemistry, 2021).
Exosomes: are hihgly enirched in specific substes of proteins, RNAs, and lipids, providing strong evdience that they are generated by an active sorting and vesciel biogenesis pathway. Once released into the extracellular milieu, exosomes can transmit signals and molecules to other cells. Consistent with their natural ability to trasfer RNAs between distinct cells, several groups have demonstrated that these bionormal nanovesicles can be laoded with synthetic small RNAs. In addition, RNA loaded exosomes can be used to deliver anti-cancer RNAs to and into tumors and tumor cells, inhibiting the expression of the target mRNAs, suppressing tumor growth and extending the lifespan of tumor-bearing animals. (Gould, “Exosome-medaited mRNA delivery in vivo is safe adn can be used to induce SARS-CoV-2 immunity” J. Biiological Chemistry, 2021).ureExo exosome isolation kit and ExoCap exosome isolation kit. (Ibrahim, US 2021/0032598).
Exosomes can be prepared uisng a commercial kit such as ExoSpin Exosome Purificaiton Kit, Invitrogen Total Exosome Purificaiton kit, P
Microvesciels: have a molecule composition that is closer to that of the cell, and there is little if any evidence for a selective biogenesis pthway for this much alrger class of EVs. (Gould, “Exosome-medaited mRNA delivery in vivo is safe adn can be used to induce SARS-CoV-2 immunity” J. Biiological Chemistry, 2021).
Proteasomes:
While proteasomes are often described as organelles, particularly in the context of their function as protein-degrading machines, they don’t quite fit the traditional definition of a membrane-bound organelle. Proteasomes are large protein complexes involved in protein degradation, and while they have specialized functions and structures, they lack the membrane enclosure that defines organelles like mitochondria or the endoplasmic reticulum.
Targeting protein degradation:
Websites: Center for Targeted Protein Degradation (working on TPD to destroy disease cuasing proteins within cells).
Introduction:
Targeted protein degradation is a therapeutic strategy that utilizes the cell’s natural machinery to eliminate disease causing proteins. Traditional drugs tend to block or inhibit a protein of interest but they do not get ride of the protein.
Degrader drugs bring the dsiease causing target prtoein into proximity with an E3 ligane – an enzyme that is part of the cell’s protein degradation machinery.
Types of TPDs:
PROTACs: Targeting protein degraders such as proteolysis-targeting chimeras (PROTACs) direct the body’s natural degradation mechanisms to eliminate the entire disease related prtoein. PROTAC is a small molcule with two ends; one end binds to the target protein of itnrest while the other binds to teh cellular machnery responsible for prtoein debrdation. In the cawse of a PROTAC, this binding involves an E3 ligase. Arvinas is using PROTAc as an estrogen receptor degrader designed to treat breast cancer (ARV-471) as well as to degrade BCL6 (ARV-393) for blood cancers. Anther involves ARV-102 which degrades a protein relvant to neuroscience.
Molecular Glues: are another type of TPD. Instead of generating entirely new prtoein-protein intereractions, as with PROTACs, molecular glues require a pre-existing surface complementarity between the two prtoeins. More specifically, they enhance the binding o the target protein to the E3 ligase, in a mechanism called gluing. Thalidonmide, lenalidomide, and pomalidomide are clinically approved molecualr glue degraders. Like PROTACs, molecualr glues are small molecuels (they lack a linker and only feature one of the two binders). They are much more minimalistic.