Peptide-Mediated Delivery of Chemical Probes and Therapeutics to Mitochondria

Abstract

Mitochondria are organelles with critical roles in key processes within eukaryotic cells, and their dysfunction is linked with numerous diseases including neurodegenerative disorders and cancer. Pharmacological manipulation of mitochondrial function is therefore important both for basic science research and eventually, clinical medicine. However, in comparison to other organelles, mitochondria are difficult to access due to their hydrophobic and dense double membrane system as well as their negative membrane potential. To tackle the challenge of targeting these important subcellular compartments, significant effort has been put forward to develop mitochondria-targeted systems capable of transporting bioactive cargo into the mitochondrial interior. Systems now exist that utilize small molecule, peptide, liposome, and nanoparticle-based transport. The vectors available vary in size and structure and can facilitate transport of a variety of compounds for mitochondrial delivery. Notably, peptide-based delivery scaffolds offer attractive features such as ease of synthesis, tunability, biocompatibility, and high uptake both in cellulo and in vivo. Owing to their simple and modular synthesis, these peptides are highly adaptable for delivering chemically diverse cargo. Key design features of mitochondria-targeted peptides include cationic charge, which allows them to harness the negative membrane potential of mitochondria, and lipophilicity, which permits favorable interaction with hydrophobic membranes of mitochondria. These peptides have been covalently tethered to target therapeutic agents, including anticancer drugs, to enhance their drug properties, and to provide probes for mitochondrial biology. Interestingly, mitochondria-targeted DNA damaging agents demonstrate high potency and the ability to evade resistance mechanisms and off-target effects. Moreover, a combination of mitochondria-targeted DNA damaging agents was applied to an siRNA screen for the elucidation of poorly understood mitochondrial DNA repair and replication pathways. In this work, a variety of novel proteins were identified that are essential for the maintenance of mitochondrial nucleic acids. Mitochondria-targeted peptides have also been used to increase the therapeutic window of antibacterial drugs with significant mammalian toxicity. Given the evolutionary similarity of mitochondria and bacteria, peptides are effective transporters that can target both of these entities. These antimicrobial peptides are highly effective even in difficult to target intracellular bacteria which reside within host cells. This peptide-based approach to targeting mitochondria has provided a variety of insights into the "druggability" of mitochondria and new biological processes that could be future drug targets. Nevertheless, the mitochondrial-targeting field is quite nascent and many exciting applications of organelle-specific conjugates remain to be explored. In this Account, we highlight the development and optimization of the mitochondria-penetrating peptides th...

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…Among these are peptides based on natural amino acid sequences targeting mitochondria and synthetic peptides, typically carrying hydrophobic (phenylalanine, tyrosine, isoleucine) and positively charged (arginine, lysine) amino acids. 112–116 Grafting the molecules of interest is possible through a peptide bond formation, making them easily tunable for diverse a range of cargo to target mitochondria for various applications. Examples of such peptides include a series of compounds known as Szeto-Schiller (SS) peptides, which are designed to deliver dimethyltyrosine (Dmt) as an antioxidant motif to mitochondria.…”

“…The ability of the MPP to deliver specific cargo into the mitochondria was confirmed experimentally. 116,129,130 Another class of mitochondria-targeted peptides is based on the partial sequence of the gramicidin S antibiotic (Chart 2). 131,132 Also, short peptides composed of two functional domains, a homing domain for cellular uptake and a proapoptotic domain targeting mitochondrial membranes, were reported and proposed for anticancer therapy.…”

Mitochondria targeting nano agents in cancer therapeutics

“…In light of this, great attention has been recently devoted to the development of a DS that is able to: i) Cross several biological barriers; ii) protect bioactive agents from premature deactivation; and iii) elevate intracellular bioavailability of the drugs at their target site (22). One of the emerging DS is represented by nanocarriers, i.e., nano-sized materials (possessing at least one dimension in the range of 1–100 nm) that can incorporate/encapsulate therapeutic compounds and be functionalized to carry multiple moieties such as imaging agents or targeting ligands at their surface.…”

ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

“…[1] However,s ide effects of chemotherapy still remain an important issue.One possibility for the solution of this problem includes the development of cancer-cell-targeting drugs.I deally,t hese drugs should have high specificity,l eading to low side effects.P reviously explored targets include macromolecules overexpressed in cancer cells for example,protein kinases [2] and receptors, [3] as well as unique features of the cancer microenvironment, for example,e levated amounts of reactive oxygen species (ROS). [6] Mitochondria targeting is currently intensely explored for development of new anticancer drugs.E xamples include antibiotic doxycycline, [7] ROS-inducer elesclomol, [8] conjugates of mitochondria-penetrating peptides (MPPs) with drugs [9] and DLCs including for example,r hodamine 123 (R123), [10] N-methylpyridinium derivative F16 [11] and dye MKT-077. [6] Mitochondria targeting is currently intensely explored for development of new anticancer drugs.E xamples include antibiotic doxycycline, [7] ROS-inducer elesclomol, [8] conjugates of mitochondria-penetrating peptides (MPPs) with drugs [9] and DLCs including for example,r hodamine 123 (R123), [10] N-methylpyridinium derivative F16 [11] and dye MKT-077.…”