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Lipase-Mediated Biocatalysis as a Greener and Sustainable Choice for Pharmaceutical Processes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Monika Sharma, Tanya Bajaj, Rohit Sharma
Cathepsin K inhibitors are an important class of antiresorptive agents that help prevent bone loss, while allowing the bone formation process to continue. Odanacatib (Fig. 1.24) is an orally bioavailable, potent, and selective cathepsin K inhibitor currently being used to treat osteoporosis. Synthesis of odanacatib relies on an enzyme resolution-mediated dynamic kinetic for the production of a key chiral fluoroleucine intermediate of odanacatib. The ring-opening ethanolysis of azlactone to form fSJ-y-fluoroleucine ethyl ester is the basic step commercially mediated by the Novozyme 435. Immobilized Candida antarctica lipase-B on an acrylic resin were also tested. In another study, CAL-B enzyme immobilized on polymethacrylate resin (CAL-B EXE120) was found to possess better stability and increased ethanolysis (Truppo and Hughes, 2011).
Recent Progress in Polymer Therapeutics as Nanomedicines
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Sahar Israeli Dangoor, Shani Koshrovski Michael, Hemda Baabur-Cohen, Liora Omer, Ronit Satchi-Fainaro
A common example is the oligopeptide spacers, which is terminated with a drug and susceptible to enzymatically catalyzed hydrolysis in the lysosomes, specifically by cathepsins B and K. The cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly was extensively used in HPMA copolymer for delivery of several anti-cancer drugs, since cathepsin B is overexpressed in many tumor cells and tumor endothelial cells [56]. This spacer is cleaved intracellularly in the lysosome, and therefore is used for drug release in the cytosol. Recently, cathepsins were also used to activate Turn-ON nano-probes. The probes were composed of non-degradable HPMA copolymer backbone conjugated to self-quenched (homo-FRET) near-infrared Cy5 dyes through the cleavable linker Gly-Phe-Leu-Gly. Upon accumulation in the tumor, overexpressed cathepsins at the tumor site cleave the dyes from the polymeric backbone and generate a fluorescence signal that will assist surgeons’ decision, in real time during surgery, regarding the tumor margins needed to be removed [57]. Another common enzymatically cleavable tetrapeptide is the Gly-Gly-Pro-Nle spacer, which is cleaved by cathepsin K. Cathepsin K is involved in bone resorption (osteoporosis, osteoarthritis and bone neoplasms), and overexpressed in bone metastases. It is localized and active in the tumor microenvironment. Cathepsin K-cleavable peptide has been used in polymer–drug conjugates to deliver drugs to bone tissues for the treatment of calcified diseases and bone metastases [25, 58, 59]. It should be noted that there are further peptide sequences, which are known to be cleaved by cathepsins, such as Phe-Lys or Val-Arg by cathepsin B [60] and Phe-Arg by cathepsins B and L [61].
Physiological aspects of blastema formation in mice
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
A second remarkable effect of HBO treatment on digit regeneration is an enhancement of bone degradation during the pre-blastema phase of regeneration (Sammarco et al. 2014, 2015). Bone degradation is an extreme example of tissue histolysis that remodels the amputation wound before blastema formation. It is reasonable to assume that all tissues involved in the regenerative response undergo some form of histolysis to establish a functional interface between the mature tissues of the stump and the newly developing tissues of the regenerate. Bone degradation involves the activity of highly specialized multinucleated cells called osteoclasts, which are derived from monocytes and attack mineralized bone. Osteoclasts attach to bone and create a focal resorptive compartment that establishes an acidic microenvironment that releases bone minerals and exposes the organic matrix of the bone for proteolytic digestion by cathepsin K, an acid protease secreted by osteoclasts. The activity of osteoclasts has been studied in the context of normal and abnormal bone turnovers, particularly in the context of bone diseases such as osteoporosis and osteopetrosis (Charles and Aliprantis 2014). During normal bone turnover, osteoclast degradation of bone is coupled with the formation of new bone tissue by osteoblasts; thus, these two cell types interact to coordinate the progressive resorption and laying down of new bone tissue in adults. Osteoclastogenesis is regulated in part by the activation of the RANK cell surface receptor (receptor activator of nuclear factor κβ) expressed by osteoclasts and its ligand, RANKL. RANK/RANKL signaling is negatively regulated by a secreted RANK decoy receptor called osteoprotegerin (OPG), which competitively binds RANKL (Honma et al. 2014).
Microstructured titanium functionalized by naringin inserted multilayers for promoting osteogenesis and inhibiting osteoclastogenesis
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Ke Shen, Xiaojing Zhang, Qiang Tang, Xingtang Fang, Chunlei Zhang, Zhaojing Zhu, Yanhua Hou, Min Lai
In order to better prove the inhibitory effect of LBL (NA) coated-Ti substrates on osteoclast formation, osteoclastic genes were measured using qRT-PCR after 7 days of culture and these results are shown in Figure 7. Cathepsin K (CTSK) encodes a member of the cysteine protease cathepsin family, which is highly expressed in osteoclasts and is involved in the degradation of collagen and other bone matrix proteins [42]. Nuclear factor of activated T cells (NFAT) is mainly expressed in immune cells and plays a key role in immune response [43]. Overexpression of TRAP is one of the main causes of osteoporosis and it is abundant in osteoclasts [41]. V-ATPase (VATP) is a specific site in the plasma membrane that is involved in the reabsorption of osteoclast attachment sites [44]. As can be seen from the Figure 7, the expression of these osteoclastic genes on LBL (NA) coated-Ti substrate decreased compared to Ti substrates. Osteoclastic genes on LBL coated-Ti substrates also decreased compared with Micro-Ti substrates to a certain extent. These results indicate that LBL (NA) coated-Ti substrates can inhibit osteoclast generation, which was inseparable from the role of NA. NA may abrogate osteoclastogenesis and bone resorption via the inhibition of RANKL-induced NF-κB and ERK activation [39].