Protein–protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies

Lucero, Bobby; Francisco, Karol R; Liu, Lawrence J.; Caffrey, Conor R.; Ballatore, Carlo

doi:10.1016/j.tips.2023.04.007

Cited by 10 publications

(6 citation statements)

References 74 publications

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“…The covalent reversible binding of small molecules to target proteins is a validated strategy in the discovery and development of pharmacological tools and candidate therapeutics that modulate PPIs. 16 The PPI between HEG1 and KRIT1 is believed to play an important role in controlling vascular development and permeability under normal and pathological conditions. 17 Genetic approaches have been instrumental in highlighting the fundamental cellular processes regulated by endothelial HEG1 and KRIT1 proteins.…”

Section: ■ Discussionmentioning

confidence: 99%

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein–Protein Interaction Inhibitors

Francisco,

Bruystens,

Varricchio

et al. 2023

ACS Pharmacol. Transl. Sci.

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The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys 720 ) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)−KRIT1 protein−protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines.

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Section: ■ Discussionmentioning

confidence: 99%

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein–Protein Interaction Inhibitors

Francisco,

Bruystens,

Varricchio

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…The evolution of PROTACs depends on existing small-molecule inhibitors, with the potential to expand their application by targeting proteins devoid of active sites for these inhibitors (Lucero et al, 2023).…”

Section: Small Molecule Protacsmentioning

confidence: 99%

“…The evolution of PROTACs depends on existing small‐molecule inhibitors, with the potential to expand their application by targeting proteins devoid of active sites for these inhibitors (Lucero et al, 2023). Although selectivity has improved, off‐target effects remain a concern, underscoring the need for further optimization (Figure 2).…”

Section: The Types Of Classic Protacsmentioning

confidence: 99%

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Zhang,

Xie,

Ran

et al. 2024

Journal Cellular Physiology

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Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch‐activated PROTACs, offering precise targeting of previously “undruggable” proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.

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“…Then, various screening strategies can be applied, including virtual screening, high throughput screening of compound libraries, fragment screening, and fragment-based drug design. Along with these strategies, a renewed interest has been focused on PPI stabilizers acting through covalent modification of specific residues because they could attain a higher duration of action and hold promise for the possible development of new drugs as well as new research tools [ 55 ]. Proteostasis-targeting chimera (PROTAC) molecules represent a striking example of successful use of this approach.…”

Section: Restoring Slc26a6 and Cftr Interaction In Cfmentioning

confidence: 99%

“…They are able to induce the proteolytic degradation of a protein of interest through proximity effects because they are formed by a ligand that binds the target protein, connected to a ligand for ubiquitin ligase [ 56 ]. The covalent stabilization of PPIs can be achieved using different methods, such as tethering strategies through disulfide bond or imine bond formation, if known ligands of the protein of interest are not available, or proximity-enabled modification of known ligands through either ligand-based chemistry or the addition of a warhead usually formed by an aldehydic group that reacts with lysine residues of the protein partner [ 55 ].…”

Section: Restoring Slc26a6 and Cftr Interaction In Cfmentioning

confidence: 99%

Unity Is Strength: The Mutual Alliance between CFTR and SLC26A6 as Therapeutic Opportunity in Cystic Fibrosis

Pariano,

Antognelli,

Romani

et al. 2024

Pharmaceuticals

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Patients with cystic fibrosis (PwCF) have recently experienced an unprecedented breakthrough with the adoption of modulator therapy in clinical practice. This remarkable achievement has led to the reconsideration of disease management as the increased life expectancy has gradually shifted the attention over a spectrum of extra-pulmonary manifestations that become prevalent in the aging population. It comes to be that complementary approaches that target patient co-morbidities are needed for the optimal clinical management of PwCF. A strategy would be to adjuvate the cystic fibrosis transmembrane conductance regulator (CFTR) in performing its functions in the different organs in which it is expressed. Solute carrier family 26 (SLC26) members appear ideal in this context. Indeed, they not only cooperate with CFTR in the organ-dependent regulation of ion fluxes but physically interact with it to reciprocally modulate their function. In this opinion, we summarize available evidence pointing to a physical and functional interaction between CFTR and SLC26 members, with a particular focus on SLC26A6 for its wider expression and broader anion selectivity, and then discuss how restoring the physical interaction between CFTR and SLC26A6 might be beneficial in the treatment of PwCF in the era of modulator therapy.

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Protein–protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies

Cited by 10 publications

References 74 publications

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein–Protein Interaction Inhibitors

Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein–Protein Interaction Inhibitors

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Unity Is Strength: The Mutual Alliance between CFTR and SLC26A6 as Therapeutic Opportunity in Cystic Fibrosis

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