A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathway <i>in vivo</i> and <i>in vitro</i>

Wang, Ping; Li, Wenying; Yang, Yumeng; Cheng, Na; Zhang, Yuchen; Zhang, Nan; Yin, Yi‐Chen; Li, Tong; Li, Zhimei; Luo, Jing

doi:10.1080/14756366.2021.1998024

Cited by 8 publications

(4 citation statements)

References 30 publications

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“…Both would be virtually impossible to reach via classical mutagenesis in a single screening round. These peptides set the basis for further optimization via in-vitro mutagenesis [ 62 ] or transfer learning [ 27 ], and/or multicomponent constructs [ 63 ] that also target the secondary LxVP binding site.…”

Section: Discussionmentioning

confidence: 99%

Funneling modulatory peptide design with generative models: Discovery and characterization of disruptors of calcineurin protein-protein interactions

Tubiana

Adriana-Lifshits²,

Nissan³

et al. 2023

PLoS Comput Biol

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Design of peptide binders is an attractive strategy for targeting “undruggable” protein-protein interfaces. Current design protocols rely on the extraction of an initial sequence from one known protein interactor of the target protein, followed by in-silico or in-vitro mutagenesis-based optimization of its binding affinity. Wet lab protocols can explore only a minor portion of the vast sequence space and cannot efficiently screen for other desirable properties such as high specificity and low toxicity, while in-silico design requires intensive computational resources and often relies on simplified binding models. Yet, for a multivalent protein target, dozens to hundreds of natural protein partners already exist in the cellular environment. Here, we describe a peptide design protocol that harnesses this diversity via a machine learning generative model. After identifying putative natural binding fragments by literature and homology search, a compositional Restricted Boltzmann Machine is trained and sampled to yield hundreds of diverse candidate peptides. The latter are further filtered via flexible molecular docking and an in-vitro microchip-based binding assay. We validate and test our protocol on calcineurin, a calcium-dependent protein phosphatase involved in various cellular pathways in health and disease. In a single screening round, we identified multiple 16-length peptides with up to six mutations from their closest natural sequence that successfully interfere with the binding of calcineurin to its substrates. In summary, integrating protein interaction and sequence databases, generative modeling, molecular docking and interaction assays enables the discovery of novel protein-protein interaction modulators.

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Section: Discussionmentioning

confidence: 99%

Funneling modulatory peptide design with generative models: Discovery and characterization of disruptors of calcineurin protein-protein interactions

Tubiana

Adriana-Lifshits²,

Nissan³

et al. 2023

PLoS Comput Biol

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“…Belatacept, a fusion protein, mimics the inhibitory receptor CTLA4 for B7, and thus blocks the co-stimulation signal ( Rangel, 2010 ). Calcineurin inhibitors block the calcineurin-dependent NFAT signaling pathway ( Wang et al., 2022 ). The second step is the transcription of different cytokine genes including that of the autocrine factor IL-2; glucocorticoids also block this step.…”

Section: Immunosuppressive Drugmentioning

confidence: 99%

Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance

Jardou,

Brossier,

Marquet

et al. 2024

Front. Cell. Infect. Microbiol.

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Transplantation is the treatment of choice for several end-stage organ defects: it considerably improves patient survival and quality of life. However, post-transplant recipients may experience episodes of rejection that can favor or ultimately lead to graft loss. Graft maintenance requires a complex and life-long immunosuppressive treatment. Different immunosuppressive drugs (i.e., calcineurin inhibitors, glucocorticoids, biological immunosuppressive agents, mammalian target of rapamycin inhibitors, and antiproliferative or antimetabolic agents) are used in combination to mitigate the immune response against the allograft. Unfortunately, the use of these antirejection agents may lead to opportunistic infections, metabolic (e.g., post-transplant diabetes mellitus) or cardiovascular (e.g., arterial hypertension) disorders, cancer (e.g., non-Hodgkin lymphoma) and other adverse effects. Lately, immunosuppressive drugs have also been associated with gut microbiome alterations, known as dysbiosis, and were shown to affect gut microbiota-derived short-chain fatty acids (SCFA) production. SCFA play a key immunomodulatory role in physiological conditions, and their impairment in transplant patients could partly counterbalance the effect of immunosuppressive drugs leading to the activation of deleterious pathways and graft rejection. In this review, we will first present an overview of the mechanisms of graft rejection that are prevented by the immunosuppressive protocol. Next, we will explain the dynamic changes of the gut microbiota during transplantation, focusing on SCFA. Finally, we will describe the known functions of SCFA in regulating immune-inflammatory reactions and discuss the impact of SCFA impairment in immunosuppressive drug treated patients.

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“…Peptide inhibitors (e.g., CN19o isolated from the inhibitor CaMKIItide) are also being developed but, while less toxic, face issues with delivery and bioavailability. As new PP2B inhibitors are being developed, cyclosporin A and tacrolimus (FK506) are currently the most effective drugs in clinical application [ 139 ]. As with most pharmaceuticals, these two have side effects.…”

Section: Final Commentsmentioning

confidence: 99%

Alzheimer’s Disease beyond Calcium Dysregulation: The Complex Interplay between Calmodulin, Calmodulin-Binding Proteins and Amyloid Beta from Disease Onset through Progression

O’Day

2023

CIMB

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A multifactorial syndrome, Alzheimer’s disease is the main cause of dementia, but there is no existing therapy to prevent it or stop its progression. One of the earliest events of Alzheimer’s disease is the disruption of calcium homeostasis but that is just a prelude to the disease’s devastating impact. Calcium does not work alone but must interact with downstream cellular components of which the small regulatory protein calmodulin is central, if not primary. This review supports the idea that, due to calcium dyshomeostasis, calmodulin is a dominant regulatory protein that functions in all stages of Alzheimer’s disease, and these regulatory events are impacted by amyloid beta. Amyloid beta not only binds to and regulates calmodulin but also multiple calmodulin-binding proteins involved in Alzheimer’s. Together, they act on the regulation of calcium dyshomeostasis, neuroinflammation, amyloidogenesis, memory formation, neuronal plasticity and more. The complex interactions between calmodulin, its binding proteins and amyloid beta may explain why many therapies have failed or are doomed to failure unless they are considered.

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A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathway in vivo and in vitro

Cited by 8 publications

References 30 publications

Funneling modulatory peptide design with generative models: Discovery and characterization of disruptors of calcineurin protein-protein interactions

Funneling modulatory peptide design with generative models: Discovery and characterization of disruptors of calcineurin protein-protein interactions

Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance

Alzheimer’s Disease beyond Calcium Dysregulation: The Complex Interplay between Calmodulin, Calmodulin-Binding Proteins and Amyloid Beta from Disease Onset through Progression

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