Structure-Based Design of Covalent Siah Inhibitors

Stebbins, John L.; Santelli, Eugenio; Feng, Yongmei; De, Surya K.; Purves, Angela; Motamedchaboki, Khatereh; Wu, Bainan; Ronai, Ze’ev A.; Liddington, Robert; Pellecchia, Maurizio

doi:10.1016/j.chembiol.2013.06.008

Cited by 48 publications

(64 citation statements)

References 46 publications

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“…Nonetheless, improving potency, selectivity, and overall drug likeness (i.e., cell permeability) of these agents remain a major challenge. More recently, introduction of covalent warheads on peptide or peptide mimetics to target Cys (de Araujo, Lim, Good, Skerlj, & Fairlie, ; Baggio et al, ; Barile et al, ; Harvey et al, ; Huhn, Guerra, Harvey, Bird, & Walensky, ; Stebbins et al, ), and more recently also Lys and Tyr residues (Baggio et al, ), is emerging strategies to increase affinity and selectivity of these agents. A large number of therapeutically viable PPIs are mediated by an alpha helix (Bullock, Jochim, & Arora, ; Sawyer, Watkins, & Arora, ), suggesting that helical peptides could in principle also be used as starting point for the design of new therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

et al. 2020

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Recently, it was reported that tetrapeptides cyclized via lactam bond between the amino terminus and a glutamic residue in position 4 (termed here N‐lock) can nucleate helix formation in longer peptides. We applied such strategy to derive N‐locked covalent BH3 peptides that were designed to selectively target the anti‐apoptotic protein Bfl‐1. The resulting agents were soluble in aqueous buffer and displayed a remarkable (low nanomolar) affinity for Bfl‐1 and cellular activity. The crystal structure of the complex between such N‐locked covalent peptide and Bfl‐1 provided insights on the geometry of the N‐locking strategy and of the covalent bond between the agent and Bfl‐1.

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Section: Introductionmentioning

confidence: 99%

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

et al. 2020

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“…Homologous sequences of the 3-D crystal structures present in the PDB were obtained by submitting the sequence of SIAH2 at PSI-Blast. Two structures, i.e., PDB-2A25 (crystal structure of SIAH1 SBD bound to the peptide) (Santelli et al, 2005) and PDB-4I7B (SIAH1 bound to synthetic peptide) (Stebbins et al, 2013), were selected using the same criteria as used during the modeling of STAT2. These crystal structures of SIAH1 (PDB IDs: 2A25 and 4I7B) were then used as templates to produce models.…”

Section: Modeling Of Siah2mentioning

confidence: 99%

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

Aslam¹,

Ahmad²,

Ali³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Dengue virus (DENV) belongs to the family Flaviviridae and can cause major health problems worldwide, including dengue fever and dengue shock syndrome. DENV replicon in human cells inhibits interferon α and β with the help of its non-structural proteins. Nonstructural protein 5 (NS5) of DENV is responsible for the proteasomemediated degradation of signal transducer and activator of transcription B. Aslam et al. 4216©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4215-4237 (2015) (STAT) 2 protein, which has been implicated in the development of resistance against interferon-mediated antiviral effect. This degradation of STAT2 primarily occurs with the help of E3 ubiquitin ligases. Seven in absentia homologue (SIAH) 2 is a host protein that can mediate the ubiquitination of proteins and is known for its interaction with NS5. In this study, comprehensive computational analysis was performed to characterize the protein-protein interactions between NS5, SIAH2, and STAT2 to gain insight into the residues and sites of interaction between these proteins. The objective of the study was to structurally characterize the NS5-STAT2, SIAH2-STAT2, and NS5-SIAH2 interactions along with the determination of the possible reaction pattern for the degradation of STAT2. Docking and physicochemical studies indicated that DENV NS5 may first interact with the host SIAH2, which can then proceed towards binding with STAT2 from the side of SIAH2. These implications are reported for the first time and require validation by wet-lab studies.

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“…Cancer Therapeutics developed a covalent peptides-based inhibitor (Cys-trapping moiety) to disrupt SIAH interactions with adaptor proteins, and thereby block cancer progression. These small molecule SIAH inhibitors are currently being tested in a preclinical phase for patients with breast, ovarian, prostate and pancreas cancers (Stebbins et al 2013 ).…”

Section: Inhibitors Of Other E3 Ubiquitin Ligasesmentioning

confidence: 98%

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

Mata-Cantero

Lobato-Gil²,

Aillet³

et al. 2014

Stress Response Pathways in Cancer

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The Ubiquitin-Proteasome System (UPS) plays an important role in the setting of the cellular response to multiple stress signals. Although the primary function of ubiquitin was initially associated with proteolysis, it is now considered as a key regulator of protein function controlling, among other functions, signalling cascades, transcription, apoptosis or oncogenesis. Failure at any level of the UPS is associated with the development of multiple pathologies including metabolic problems, immune diseases, infl ammation and cancer. The successful use of the proteasome inhibitor Bortezomib (Velcade) in the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) revealed the potential of the UPS as pharmacological target. Ten years later, new inhibitors tackling not only the proteasome but also different subsets of enzymes which conjugate or de-conjugate ubiquitin or ubiquitin-like molecules, have been developed. Most of them are excellent tools to characterize better the emerging molecular mechanisms regulating distinct critical cellular processes. Some of them have been launched already while many others are still in pre-clinical development. This chapter updates some of the most successful efforts to develop and characterize inhibitors of the UPS which tackle mechanisms involved in cancer. Particular attention has been dedicated to updating the status of the clinical trials of these inhibitors.

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Structure-Based Design of Covalent Siah Inhibitors

Cited by 48 publications

References 46 publications

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

The Ubiquitin-Proteasome System (UPS) as a Cancer Drug Target: Emerging Mechanisms and Therapeutics

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