Enhanced interrogation: emerging strategies for cell signaling inhibition

Huang, Rong; Martinez-Ferrando, Isabel; Cole, Philip A.

doi:10.1038/nsmb0610-646

Cited by 15 publications

(12 citation statements)

References 45 publications

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“…It is well known that finding activating reagents is more difficult than finding inhibitory ones since the latter has the clear target of the substrate-binding site. Therefore, a lot of inhibitory reagents have been developed but far fewer activating ones [ 4 , 5 , 20 , 21 ]. The SF- (substrate-function-) link method developed recently [ 13 ] has the potential to select protease-activating peptides if it is operated in the inverse mode owing to its construction design (see Figure 1 ), and this technique has been successfully exploited for the first time in this paper.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Selection of Cathepsin E-Activity-Enhancing Peptide Aptamers at Neutral pH

Biyani

Futakami

Kitamura

et al. 2011

International Journal of Peptides

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The aspartic protease cathepsin E has been shown to induce apoptosis in cancer cells under physiological conditions. Therefore, cathepsin E-activity-enhancing peptides functioning in the physiological pH range are valuable potential cancer therapeutic candidates. Here, we have used a general in vitro selection method (evolutionary rapid panning analysis system (eRAPANSY)), based on inverse substrate-function link (SF-link) selection to successfully identify cathepsin E-activity-enhancing peptide aptamers at neutral pH. A successive enrichment of peptide activators was attained in the course of selection. One such peptide activated cathepsin E up to 260%, had a high affinity (KD; ∼300 nM), and had physiological activity as demonstrated by its apoptosis-inducing reaction in cancerous cells. This method is expected to be widely applicable for the identification of protease-activity-enhancing peptide aptamers.

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Section: Discussionmentioning

confidence: 99%

In Vitro Selection of Cathepsin E-Activity-Enhancing Peptide Aptamers at Neutral pH

Biyani

Futakami

Kitamura

et al. 2011

International Journal of Peptides

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“…Signal cascades exist for the amplification of a small signal into a large response, leading to significant cellular changes such as expression of specific genes, the activity of certain proteins, or changes in cell cycle progression. Many disease processes, such as diabetes, heart disease, autoimmunity and cancer, arise from defects in signal transduction pathways, further highlighting the critical importance of signal transduction to biology as well as the development of medicine ( Huang et al, 2010 ). Cyclic AMP levels in most eukaryotes are increased by stimulation of adenylyl cyclases (ACs), whilst cyclic nucleotide PDEs degrade the phosphodiester bond in cAMP, thereby limiting or abrogating signal transduction.…”

Section: Signal Transduction In Trypanosomatidsmentioning

confidence: 99%

The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

2015

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Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics.

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“…An opposite strategy has fascinated scientists for decades: stabilizing or forming de novo PPIs with interfacial molecules, also called "molecular glues" [4,5]. By bringing together two proteins that would not normally interact, control can be gained in principle over protein fate, localization and function, impacting cellular signalling [6]. Bifunctional chimeric molecules, composed of two binding units often referred to as chemical inducers of dimerization (CIDs) or chemical inducers of proximity (CIPs), enable recruitment of two targets simultaneously [7,8].…”

Section: Introductionmentioning

confidence: 99%

Bifunctional chemical probes inducing protein–protein interactions

Maniaci

Ciulli

2019

Current Opinion in Chemical Biology

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Stabilizing biomolecular interactions with synthetic molecules to impact biological function is a concept of enormous appeal. Although much effort has been devoted to disrupting proteinprotein interactions (PPIs) using inhibitors, less attention has been directed toward the reverse strategy, that of inducing new PPIs. However recent years have seen a resurgence of interest in designing molecules that bring proteins together. This approach promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention. Pioneering structural and biophysical investigation of ternary complexes formed by mono-and bifunctional ligands highlight that proximity-induced stabilization or de novo formation of PPIs are a common feature of their molecular recognition. In this review, we illustrate these concepts and advances with representative case studies, and highlight progress over the past three years, with particular focus on recruitment to E3 ubiquitin ligases by "molecular glues" and chimeric dimerizers (PROTACs) for targeted protein degradation.

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Enhanced interrogation: emerging strategies for cell signaling inhibition

Cited by 15 publications

References 45 publications

In Vitro Selection of Cathepsin E-Activity-Enhancing Peptide Aptamers at Neutral pH

In Vitro Selection of Cathepsin E-Activity-Enhancing Peptide Aptamers at Neutral pH

The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

Bifunctional chemical probes inducing protein–protein interactions

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