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Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
An alternative approach is downregulation of the target protein, which should have a potential therapeutic effect. Recently, we and others have developed a protein knockdown technology that induces degradation of target proteins using hybrid small molecules named SNIPERs [specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers] or PROTACs (proteolysis targeting chimeras). They are chimeric molecules consisting of two different ligands connected by a linker. One ligand is for the target protein, while the other is for E3 ubiquitin ligases. Accordingly, these molecules are expected to crosslink the target protein and E3 ubiquitin ligases in cells, resulting in ubiquitylation and subsequent degradation of the target protein via the ubiquitin-proteasome system (UPS) (Fig. 16.1). In this chapter, we present examples of drugs that act by degrading oncogenic proteins, and discuss the features and prospect of chemical degraders.
Engineered flies for regeneration studies
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
In Drosophila, many signaling pathways converge into one apoptotic program, in which inhibitors of apoptosis and activators interplay to balance the death/live fate of a cell (Bergmann and Steller 2010). Cells have commonly inhibited the apoptotic pathway by the action of the inhibitor of apoptosis (IAP) proteins. The IAPs directly bind to caspases through the baculovirus IAP repeat (BIR) domain, thereby inhibiting their activation (Salvesen and Duckett 2002). Drosophila IAP (Diap1) can be inhibited by the family of IAP antagonists Reaper (Rpr), Hid and Grim proteins, initially discovered in flies (Goyal et al. 2000). This family of Diap1 inhibitors contains IAP-binding motifs (IBM) that are required to bind the BIR domains and hamper the anti-apoptotic function of IAP, thereby releasing the caspases from Diap1 (Sandu et al. 2010). Therefore, inducible expression of these Diap1 antagonists, mostly Hid and Rpr, has become a convenient way to induce apoptosis.
Boolean Networks
Published in Haitao Li, Guodong Zhao, Peilian Guo, Zhenbin Liu, Analysis and Control of Finite-Value Systems, 2018
Haitao Li, Guodong Zhao, Peilian Guo, Zhenbin Liu
where the concentration level (high or low) of the inhibitor of apoptosis proteins (IAP) is denoted by x1, the concentration level of the active caspase 3 (C3a) $ ({\text{C3a}}) $ by x2, and the concentration level of the active caspase 8 (C8a) by x3; the concentration level of the tumor necrosis factor (TNF, a stimulus) is regarded as the control input u.
Does a jammer-type racing swimsuit improve sprint performance during maximal front-crawl swimming?
Published in Sports Biomechanics, 2021
Shin-Ichiro Moriyama, Hirotoshi Mankyu, Takaaki Tsunokawa, Tsubasa Kurono, Hayato Mizukoshi, Futoshi Ogita
IAP (kPa) was determined by measuring the rectal pressure using MPC-500 catheter-type pressure transducer (1.6-mm diameter; Millar Instruments, TX, USA) placed intra-rectally, approximately 15 cm from the anus (Moriyama et al., 2014a, 2014b). Intra-rectal IAP measured at ≥10 cm from the anus is almost the same as that measured using laparoscopy (McCarthy, 1982). The pressure transducer was fitted with a rubber probe cover (P249; Nikkiso-YSI, Musashino, Japan) to prevent contamination. Based on previous studies (Moriyama et al., 2014a, 2014b), small holes were pierced into the probe cover at several places to prevent any trapped air acting as a pressure buffer. The transducer and connector, which connects the transducer with the pressure sensor, were waterproofed using waterproof plastic and tape to prevent electric leakage. The pressure transducer was inserted by the participants themselves, and it was confirmed that IAP rose noticeably because of coughing or other responses, without effects on the anal sphincter.
The effects of the muscular contraction on the abdominal biomechanics: a numerical investigation
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2019
Piero G. Pavan, Silvia Todros, Paola Pachera, Silvia Pianigiani, Arturo N. Natali
The abdominal wall is subject to the adaptable intra-abdominal pressure (IAP) that directly depends on the variable volumes of the internal organs, breathing, and muscle activation. Different pathologies are related to abnormal effects of IAP and to the mechanical characteristics of abdominal wall structures, highlighting the relevance of the biomechanical properties of this region. An increase in IAP can have negative effects: decreased cardiac output due to reduced venous return, decreased renal blood flow, glomerular filtration rate and reduced splanchnic and hepatic perfusion (Cobb et al. 2005). High values of IAP have direct consequences, together with other factors, in the formation and recurrence of abdominal hernias. As concerning this aspect, the evaluation of the forces exerted on the fascial structures in the healthy abdomen during the execution of different daily tasks represents an issue of considerable clinical interest.