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Medical Countermeasures for Intoxication by Botulinum Neurotoxin
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Michael Adler, Ajay K. Singh, Nizamettin Gul, Frank J. Lebeda
Because metalloprotease inhibitors are still in early development, and as yet, no practical methods to reduce light chain persistence have emerged, the therapies described, aimed at increasing transmitter release, offer a more rapid pathway for treatment of BoNT/A intoxication. For iatrogenic botulism, which is usually less severe than natural outbreaks, PB may represent a safe and effective symptomatic treatment.
Mechanisms of Tumor Cell Invasion studied In Vitro
Published in Rolf Bjerkvig, Spheroid Culture in Cancer Research, 2017
Utilizing a modification of the substrate-gel electrophoresis technique, inhibitors of proteases are identifiable (reverse zymograms).78 Conditioned medium or cell membrane preparations are separated on substrate-impregnated Polyacrylamide gels, as in the conventional protease assay, except that after the proteins have been separated, the entire gel is processed for digestion with protease. At those locations to which protease inhibitors have migrated, the substrate is spared digestion, and the gel stains intensly.78 This method has recently identified novel metalloprotease inhibitors from human glioma cells.76
Human Herpesvirus Type 8/Kaposi Sarcoma Herpesvirus
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Hiba El Hajj, Raghida Abou Merhi, Ali Bazarbachi
The prognosis for HHV-8 associated diseases remains poor, and currently used treatment modalities are far from achieving complete and sustainable remission. Indeed, the persistent global burden of KS and the few successful strategies of treatment in MCD and PEL suggest that novel effective drugs are badly needed. Based on recent preclinical data and translational studies, several new targeted therapies have been found promising. These include inhibitors of viral replication (zidovudine and interferon, HAART), modulators of cell signaling and inflammation (interferon), immunomodulators (thalidomide), monoclonal antibodies (rituximab) and inhibitors of angiogenesis (bevacizumab), NF-κB inhibitors such as arsenic trioxide or proteasome inhibitors (bortezomib), histone deacetylase inhibitors (SAHA), metalloprotease inhibitors (COL-3), and TKI (imatinib). However, the efficacy of these strategies can only be validated through careful controlled clinical trials. Some of these targeted therapies have not yet reached clinical studies, although others were used in a few individual case reports with low numbers of patients.
Epidermal growth factor receptor ligands: targets for optimizing treatment of metastatic colorectal cancer
Published in Growth Factors, 2019
Siavash Foroughi, Jeanne Tie, Peter Gibbs, Antony Wilks Burgess
In mouse embryonic cells, ADAM17, also known as Tumour-Necrosis Factor-α converting enzyme (TACE), is the main sheddase for EREG, TGF-α, AREG, HB-EGF, and the neuregulins, however, it is unclear if ADAM19 also plays a role in neuregulin processing (Horiuchi et al. 2005; Kurohara et al. 2004). ADAM10 appears to be responsible for the shedding and activation of EGF and BTC (Sahin et al. 2004). Although juxtacrine signaling by membrane-bound EGFR ligands, such as TGF-α, has been observed (Anklesaria et al. 1990), metalloprotease activity is required for autocrine and paracrine signaling to occur (Gee and Knowlden 2003). Metalloprotease-dependent EGFR-family signaling can be disrupted by protease inhibitors, eloquently demonstrated using the metalloprotease inhibitor Batimastat (BB-94) (Dong et al. 1999). This inhibitor blocks EGFR-dependent cell proliferation and migration of human mammary epithelial cells, i.e. the growth of primary tumors and the migration of cells into metastatic sites. Cell proliferation was inhibited in direct proportion to the inhibition of EGF release and the consequential signaling, however, the inhibition of autocrine ligand stimulated proliferation and migration by the protease inhibitors is rescued by exogenous EGF (Dong et al. 1999).
Synthesis and structure–activity relationships of pyrazole-based inhibitors of meprin α and β
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Kathrin Tan, Christian Jäger, Stefanie Geissler, Dagmar Schlenzig, Mirko Buchholz, Daniel Ramsbeck
The abovementioned roles in pathophysiology suggest meprin α and β as valuable drug targets, but further target validation is needed to shed light on their individual contribution to the onset of diseases and potential treatment options. For this purpose, highly potent and selective inhibitors are required that could serve as lead compounds for preclinical development and/or chemical probes to elucidate the impact of pharmacological modulation of meprin activity on disease progression. However, no inhibitor of either meprin α or β has entered clinical trials, yet. In general, the development of metalloprotease inhibitors, in particular MMP inhibitors, was impaired in the past and the occurrence of undesired side-effects led to the discontinuation of clinical development34. Most metalloprotease inhibitors rely on a hydroxamic acid moiety as zinc chelating group. However, due to the strong hydroxamate-zinc interaction this could cause inhibition of other metalloproteases and also other zinc-depending enzymes. In consequence, this unselective off-target inhibition can lead to the observed side effects35. Hence, it is of particular importance to monitor the inhibition of related enzymes during the development of metalloprotease inhibitors. Potent inhibitors of both meprin isoenzymes are already known (Figure 1). The first inhibitors of meprins have been reported by Kruse et al., e.g. the naturally occurring Actinonin (1) or the broad spectrum metalloprotease inhibitor NNGH (4a)27. Later, novel chemotypes have been identified by high throughput screening (2 and 3)36. The first systematic elaboration of structure–activity relationship (SAR) using NNGH as lead structure led to the development of potent sulfonamide (4b) and tertiary amine based inhibitors (5a,b)37–39. The latter exhibit favourable inhibition of either meprin β or α, respectively. Notably, these inhibitors also contain a hydroxamic acid moiety as zinc-chelating functionality, bearing the abovementioned potential risk of unselective off-target inhibition. Nevertheless, they exhibit a superior selectivity profile against off-target metalloproteases, a prerequisite for further development and a potential clinical application. The SAR of the sulphonamide and tertiary amine based inhibitors revealed the importance of an acidic scaffold decoration to achieve potent inhibition of meprin β37,38,40. This corroborates its substrate specificity, with a high preference of acidic amino acids in P1 and P1′-position of the respective substrates. This is mediated by a cluster of positively charged arginine residues in the active site cleft, forming the S1, S1′, and S2′ pocket, respectively41. Although the S1′-pocket in meprin α comprises an arginine as well, the prevalence for acidic substrates is less pronounced, due to differing amino acids shaping the S1 and S2′ pockets, i.e. tyrosine residues41,42. This also translates into the structural requirements for meprin α inhibitors, being less acidic and also neutral moieties could lead to sufficient activity.