A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Haugaard‐Kedström, Linda M.; Clemmensen, Louise S.; Sereikaitė, Vita; Jin, Zeyu; Fernandes, Eduardo Felipe Alves; Wind, Bianca; Abalde-Gil, Flor; Daberger, Jan; Vistrup-Parry, Maria; Aguilar-Morante, Diana; Leblanc, Raphaël; Egea-Jimenez, Antonio Luis; Albrigtsen, Marte; Jensen, Knud; Jensen, Torben Pilegaard; Ivarsson, Ylva; Vincentelli, Renaud; Hamerlik, Petra; Andersen, Jeanette H.; Zimmermann, Pascale; Lee, Weontae; Strømgaard, Kristian

doi:10.1021/acs.jmedchem.0c00382

Cited by 13 publications

(23 citation statements)

References 48 publications

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“…The inhibitor appears to specifically block SARS-CoV-2 entry by the endosomal pathway as it was highly effective on VeroE6 cells that lacks TMPRSS2, but failed to inhibit infection of Calu-3 cells that expresses TMPRSS2, which enables SARS-CoV to fuse at the plasma membrane [30]. The KSL-128114 inhibitor has previously been shown to have a negative effect on syntenin-dependent endosomal budding through binding to syntenin PDZ1 [18]. The impairment of the PDZ1 binding pocket has further been shown to lead the co-accumulation of syntenin and syndecan in a recycling compartment [8].…”

Section: Discussionmentioning

confidence: 99%

A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses

Lindqvist

Benz

Sereikaitė

et al. 2022

Preprint

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Viruses are dependent on interactions with host factors in order to efficiently establish an infection and replicate. Targeting such interactions provides an attractive strategy to develop novel antivirals. Syntenin is a protein known to regulate the architecture of cellular membranes by its involvement in protein trafficking, and has previously been shown to be important for HPV infection. Here we show that a highly potent and metabolically stable peptide inhibitor that binds to the PDZ1 domain of syntenin inhibits SARS-CoV-2 infection by blocking the endosomal entry of the virus. Furthermore, we found that the inhibitor also hampered chikungunya infection, and strongly reduced flavivirus infection, which are completely dependent on receptor mediated endocytosis for their entry. In conclusion, we have identified a novel pan-viral inhibitor that efficiently target a broad range of RNA viruses.

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Section: Discussionmentioning

confidence: 99%

A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses

Lindqvist

Benz

Sereikaitė

et al. 2022

Preprint

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“…Previous studies described some of these molecules related to brain tumors, although their secretion mechanism is not fully understood. For example, the scaffold protein called syntenin, which contains two postsynaptic density protein-95/discs-large/PDZ domains, also presents as a potential new therapeutic target in GBM ( Haugaard-Kedstrom et al, 2021 ). The highly selective inhibitor of syntenin KSL-128114 can bind to the PDZ1 domain of syntenin and demonstrates a decrease in cell viability of primary GBM cells and significantly increases survival in patient-derived xenograft mouse models ( Haugaard-Kedstrom et al, 2021 ).…”

Section: Unconventional Protein Secretion In Brain Tumorsmentioning

confidence: 99%

“…For example, the scaffold protein called syntenin, which contains two postsynaptic density protein-95/discs-large/PDZ domains, also presents as a potential new therapeutic target in GBM ( Haugaard-Kedstrom et al, 2021 ). The highly selective inhibitor of syntenin KSL-128114 can bind to the PDZ1 domain of syntenin and demonstrates a decrease in cell viability of primary GBM cells and significantly increases survival in patient-derived xenograft mouse models ( Haugaard-Kedstrom et al, 2021 ). Additionally, specific inhibition of syntenin activity by the PDZ1 inhibitor decreases radioresistance of human GBM cells and decreases invasion post-radiotherapy ( Kegelman et al, 2017 ).…”

Section: Unconventional Protein Secretion In Brain Tumorsmentioning

confidence: 99%

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

Iglesia

Prado

Alves

et al. 2022

Front. Cell Dev. Biol.

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Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.

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“…A recent work by Haugaard-Kedström and co-workers reported the design of new monomeric peptides (KLS-128018, KSL-128114) able to bind PDZ1 of Syntenin in a non-canonical way with high affinity. These Peptides showed a promising effect against highly aggressive cancer forms, such as glioblastoma (GBM) [ 59 ].…”

Section: Role Of Pdz-containing Proteins In Human Diseasesmentioning

confidence: 99%

“…Since 1996, when it was reported the first peptide able to bind a PDZ domain [ 180 ] more than 600 papers about PDZ inhibitors were published (source SciFinder). Among them, many remarkable results were reported such as the PDZ inhibitors of PSD-95 [ 181 ], Synthenin [ 59 ] and Dvl [ 69 , 70 ]. More than 600 crystal structures of human PDZ domains available at the protein data bank (ww.rcsb.org) have brought significant insight into the rational design of PDZ modulators.…”

Section: Pdz Inhibitorsmentioning

confidence: 99%

Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

et al. 2021

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The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo.

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A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Cited by 13 publications

References 48 publications

A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses

A syntenin inhibitor blocks endosomal entry of SARS-CoV-2 and a panel of RNA viruses

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression

Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

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