Lemay Receptor tyrosine kinases (RTKs) regulate critical physiological processes, such as cell growth, survival, motility, and metabolism. Abnormal activation of RTKs and relative downstream signaling is implicated in cancer pathogenesis. Phage display allows the rapid selection of peptide ligands of membrane receptors. These peptides can target in vitro and in vivo tumor cells and represent a novel therapeutic approach for cancer therapy. Further, they are more convenient compared to antibodies, being less expensive and non-immunogenic. In this review, we describe the state-of-the-art of phage display for development of peptide ligands of tyrosine kinase membrane receptors and discuss their potential applications for tumor-targeted therapy.
Phage display represents a useful technique for studying protein–protein interactions that regulate the biological processes. Bacteriophages, which are viruses infecting bacteria, can express recombinant peptides on their surface coat following the cloning of random short DNA sequences within their genome. The phage display technique was first described in 1985 by George P. Smith, who demonstrated the expression of a foreign insert on a filamentous phage surface following its cloning in frame with the minor coat protein pIII. In the same year, George Pieczenik patented the production of random peptide libraries for phage display (US Patent, 5,866,363). In 1988, the selection of phage ligands of target proteins was improved by using a process called “biopanning”, which significantly reduced antibody requirements compared to the original procedure published in 1985. In the 1990s, combinatorial phage libraries containing 40 million 6-mer peptides or 20 million 15-mer peptides were built. As predicted by Smith, the use of these libraries allowed an effective investigation of the specific affinity binding to antibody epitopes, receptors, or other proteins using simple recombinant DNA methods. What Smith did not imagine was the wide number of applications of his invention in various biomedical fields. The phage display technology was further developed and improved by the following research teams: G. Winter and J. McCafferty of the Medical Research Council, Laboratory of Molecular Biology; R. Lerner and C. Barbas of the Scripps Research Institute; F. Breitling and S. Dübel of the German Cancer Research Center. All these researchers pursued the creation of phage-displayed combinatorial antibodies libraries, which were further improved by several other laboratories in the following years. As recognition of the phage display contribution to scientific advances in chemistry and pharmaceutics, George P. Smith and Sir Gregory P. Winter received the 2018 Nobel Prize in Chemistry “for phage visualization of peptides and antibodies”. More recently, the phage display has been useful for the mapping of antibody binding epitope and the screening of combinatorial peptide libraries in drugs discovery. A timeline of phage display development is shown below. (Viruses . 2021 Apr 9;13(4):649.)
Coenzyme Q10 (CoQ10 or ubiquinone) is a mobile proton and electron carrier of the mitochondrial respiratory chain with antioxidant properties widely used as an antiaging health supplement and to relieve the symptoms of many pathological conditions associated with mitochondrial dysfunction. Even though the hegemony of CoQ10 in the context of antioxidant-based treatments is undeniable, the future primacy of this quinone is hindered by the promising features of its numerous analogues. Despite the unimpeachable performance of CoQ10 therapies, problems associated with their administration and intraorganismal delivery has led clinicians and scientists to search for alternative derivative molecules. Over the past few years, a wide variety of CoQ10 analogues with improved properties have been developed. These analogues conserve the antioxidant features of CoQ10 but present upgraded characteristics such as water solubility or enhanced mitochondrial accumulation. Moreover, recent studies have proven that some of these analogues might even outperform CoQ10 in the treatment of certain specific diseases. The aim of this review is to provide detailed information about these Coenzyme Q10 analogues, as well as their functionality and medical applications.
Overall, the beneficial effects of CoQ10 on human health and disease treatment are well known. However, there is growing interest among the scientific community for CoQ10 analogues and their presumably optimized performance in antioxidant therapies. In this review we have outlined the chemical improvements that successfully enhance CoQ10 bioavailability: shortening of its isoprenoid chain (idebenone and short chain CoQ analogues); addition of specific radicals to promote its mitochondrial accumulation (mitoquinone); modification of natural analogs to boost their antioxidant effect (plastoquinone); modification of the quinone ring (C6 modifications); and introduction of changes on its isoprenoid chain (decylubiquinone) to diversify its biology, its hybridization with other antioxidants and to enhance its potency (EPI-743). Taken together, these synthetic CoQ10 analogues open the door to new and improved therapies for conditions ranging from mitochondrial diseases to cancer. (Antioxidants (Basel). 2021 Feb; 10(2): 236.)
Hypoxic-ischemic encephalopathy (HIE), initiated by the interruption of oxygenated blood supply to the brain, is a leading cause of death and lifelong disability in newborns. The pathogenesis of HIE involves a complex interplay of excitotoxicity, inflammation, and oxidative stress that results in acute to long term brain damage and functional impairments. Therapeutic hypothermia is the only approved treatment for HIE but has limited effectiveness for moderate to severe brain damage; thus, pharmacological intervention is explored as an adjunct therapy to hypothermia to further promote recovery. However, the limited bioavailability and the side-effects of systemic administration are factors that hinder the use of the candidate pharmacological agents. To overcome these barriers, therapeutic molecules may be packaged into nanoscale constructs to enable their delivery. Yet, the application of nanotechnology in infants is not well examined, and the neonatal brain presents unique challenges. Novel drug delivery platforms have the potential to magnify therapeutic effects in the damaged brain, mitigate side-effects associated with high systemic doses, and evade mechanisms that remove the drugs from circulation. Encouraging pre-clinical data demonstrates an attenuation of brain damage and increased structural and functional recovery. This review surveys the current progress in drug delivery for treating neonatal brain injury. (Journal of Controlled Release., Volume 330, 10 February 2021, Pages 765-787.)
A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age-associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin-protective compound as a therapeutic agent. SS-31 is a member of the Szeto-Schiller (SS) peptides known to selectively target the inner mitochondrial membrane. SS-31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS-31 prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. As a result, SS-31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS-31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of SS-31 and provides an update of its clinical development programme. (Br J Pharmacol. 2014 Apr;171(8):2029-50.)
It was the aim of this study to investigate a novel strategy for oral gene delivery utilizing a self-nanoemulsifying drug delivery system (SNEDDS). After hydrophobic ion pairing a plasmid was incorporated into SNEDDS. The mean droplet size of resulting nanoemulsions was determined to be between 45.8 and 47.5 nm. A concentration dependent cytotoxicity of the formulations was found on HEK-293 cells via MTT assay. Degradation studies via DNase I showed that incorporation into SNEDDS led to significantly, up to 8-fold prolonged resistant time against enzymatic digestion compared to naked pDNA and pDNA–lipid complexes. Transfection studies carried out revealed a significantly improved transfection compared to naked pDNA. Further, no decrease in transfection efficiency compared to transfection using Lipofectin® transfection reagent was observed. (International Journal of Pharmaceutics. Volume 487, Issues 1–2, 20 June 2015, Pages 25-31.)
The objective of this study was to investigate the impact of different hydrophobic ion pairs (HIP) on the oral bioavailability of the model drug octreotide in pigs.
Octreotide was ion paired with the anionic surfactantsdeoxycholate, decanoate and docusate differing in lipophilicity. These hydrophobic ion pairs were incorporated in self-emulsifying drug delivery systems (SEDDS) based on BrijO10, octyldodecanol, propylene glycol and ethanol in a concentration of 5 mg/ml. SEDDS were characterized regarding size distribution, zeta potential, stability towards lipase, log DSEDDS/release medium and mucus diffusion behavior. The oral bioavailability of octreotide was evaluated in pigs via LC-MS/MS analyses.
Most efficient ion pairing was achieved at a molar ratio of 1:3 (peptide: surfactant). SEDDS containing the octreotide-deoxycholate, -decanoate and -docusate ion pair exhibited a mean droplet size of 152 nm, 112 nm and 191 nm and a zeta potential of − 3.7, − 4.6 and − 5.7 mV, respectively. They were completely stable towards degradation by lipase and showed a log DSEDDS/release medium of 1.7, 1.8 and 2.7, respectively. The diffusion coefficient of these SEDDS was in the range of 0.03, 0.11 and 0.17 × 10− 9 cm2/s, respectively. In vivo studies with these HIPs showed no improvement in the oral bioavailability in case of octreotide-decanoate. In contrast, octreotide-deoxycholate and octreotide-docusate SEDDS resulted in a 17.9-fold and 4.2-fold higher bioavailability vs. control.
According to these results, hydrophobic ion pairing could be identified as a key parameter for SEDDS to achieve high oral bioavailability. (Journal of Controlled Release. Volume 273, 10 March 2018, Pages 21-29.)
Polymer–drug conjugates (PDC) have exhibited clinical and commercial success in the field of drug delivery. A polymeric backbone, linker, targeting moiety, and drug constitute the building blocks of PDCs. Current attention is focusing on natural polymeric carriers, in particular the concept of graft copolymers, such as a combination of polymers and polysaccharides, to explore dual benefits such as combined vehicles and targeting moieties. Polymer heterogeneity, synthesis of PDCs, broad molecular weight distribution, conjugate variability, immunogenicity of polymers, safety, stability, and stringent regulatory approval are the major obstacles to the successful transition of PDCs to the clinic. In this review, we discuss natural and synthetic PDCs combined with computational modeling for diverse pharmaceutical and biomedical applications. (Drug Discovery Today. Volume 25, Issue 9, September 2020, Pages 1718-1726.)
Novel cosmeceutical ingredients from plant sources are in huge demand by the personal care products manufacturing industry due to the growing consumer awareness about healthy products with natural ingredients. The advancements in the understanding of the skin physiology and ageing resulted in the identification of novel biochemical targets of skin health, chemical manipulation of which has the potential to regain and/or remain in a healthy state. Plants are the chief source of such phytochemicals which can alter or bring back the original healthy skin and external appearance. A number of plants have been used by the industry to create novel cosmeceutical formulations with specific objectives such as sun protection, anti-ageing, anti-wrinkling, anti-oxidant, anti-allergy. Plants growing in adverse environmental climates are being explored, evaluated and converted into novel products by the cosmeceutical industry. The current review aims at the novel plant sources which are utilized by the various industry leaders in the business and their scientific rationale for their cosmeceutical applications. Around 68 plant sources used by the industry belonging to the six major plant families, Asteraceae, Lamiaceae, Fabaceae, Poaceae, Malvaceae and Rosaceae are reviewed scientifically for their cosmeceutical claims. (Journal of Applied Research on Medicinal and Aromatic Plants. Volume 7, December 2017, Pages 1-26.)