Expanding the Known Structure Space for RNA Binding: A Test of 2,5-Diketopiperazine

2022 ◽  
Author(s):  
Diego Arévalo ◽  
Viktoriya Anokhina ◽  
Oliver Swart ◽  
Benjamin Locke Miller
Keyword(s):  
Therapeutic Target ◽  
Rna Binding ◽  
Structure Space

As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines...

scholarly journals Sam68 promotes hepatic gluconeogenesis via CRTC2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aijun Qiao ◽  
Junlan Zhou ◽  
Shiyue Xu ◽  
Wenxia Ma ◽  
Chan Boriboun ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Adaptor Protein ◽  
Diabetic Mouse ◽  
Mrna Levels ◽  
Hepatic Gluconeogenesis ◽  
Kinase Substrate ◽  
Glucose Levels ◽  
Patients With Diabetes

AbstractHepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.

Abstract B30: The RNA-binding protein LARP1 is a cancer therapeutic target

2017 ◽  
Author(s):  
Essam A. Ghazaly ◽  
John Le Quesne ◽  
Dahai Jiang ◽  
Selanere L. Mangala ◽  
James Chettle ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein

scholarly journals L523S, an RNA-binding protein as a potential therapeutic target for lung cancer

2003 ◽  
Vol 88 (6) ◽  
pp. 887-894 ◽  
Author(s):  
T Wang ◽  
L Fan ◽  
Y Watanabe ◽  
P D McNeill ◽  
G G Moulton ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Potential Therapeutic Target

Sequence and structure space of RNA-binding peptides

Biopolymers ◽  
2003 ◽  
Vol 70 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Chandreyee Das ◽  
Alan D. Frankel
Keyword(s):  
Rna Binding ◽  
Structure Space ◽  
Binding Peptides

HuR as Therapeutic Target in Cancer: What the Future Holds

2021 ◽  
Vol 28 ◽  
Author(s):  
Dimitrios Goutas ◽  
Alexandros Pergaris ◽  
Constantinos Giaginis ◽  
Stamatios Theocharis
Keyword(s):  
Therapeutic Target ◽  
Rna Binding ◽  
Cancer Therapeutics ◽  
Scientific Data ◽  
Promising Target ◽  
Pubmed Database ◽  
Increased Risk ◽  
Major Player

: ELAV-like protein 1, or HuR (human antigen R), is an RNA-binding protein encoded by the ELAVL1 gene in humans. One of its best functions is to stabilize mRNAs in order to regulate gene expression. HuR protein overexpression has undoubtedly been linked to an increased risk of tumor growth, progression, and metastasis, rendering it a potential therapeutic target candidate in cancer. Novel agents interfering with HuR expression have been tested, both in vitro and in vivo, with promising results. The aim of this paper is to review the existing literature regarding the potential agents that could actively act on and inhibit HuR expression. HuR molecule controls the expression of various proto-oncogenes, cytokines and growth factors, representing a major player in tumor progression, invasion, and metastasis and constituting an emerging target for cancer therapy. PubMed database was thoroughly searched, and all published articles providing scientific data on molecules that can exhibit antitumorigenic effects via HuR inhibition were included. According to these data, HuR inhibition should be a promising target in cancer therapeutics.

scholarly journals Interplay between RNA-binding protein HuR and Nox4 as a novel therapeutic target in diabetic kidney disease

2020 ◽  
Vol 36 ◽  
pp. 100968 ◽  
Author(s):  
Qian Shi ◽  
Doug-Yoon Lee ◽  
Denis Féliers ◽  
Hanna E. Abboud ◽  
Manzoor A. Bhat ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Therapeutic Target ◽  
Diabetic Kidney Disease ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Diabetic Kidney ◽  
Novel Therapeutic

scholarly journals RNA binding motif protein 3: a potential biomarker in cancer and therapeutic target in neuroprotection

Oncotarget ◽  
2017 ◽  
Vol 8 (13) ◽  
pp. 22235-22250 ◽  
Author(s):  
Ren-Bin Zhou ◽  
Xiao-Li Lu ◽  
Chen-Yan Zhang ◽  
Da-Chuan Yin
Keyword(s):  
Therapeutic Target ◽  
Rna Binding ◽  
Binding Motif ◽  
Potential Biomarker

Progesterone Receptor Membrane Component 1 and Its Accomplice: Emerging Therapeutic Targets in Lung Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Solaipriya Solairaja ◽  
Satish Ramalingam ◽  
Nageswara Rao Dunna ◽  
Sivaramakrishnan Venkatabalasubramanian
Keyword(s):  
Lung Cancer ◽  
Progesterone Receptor ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Binding Protein ◽  
Synaptic Function ◽  
Membrane Component ◽  
Mitochondrial Energy Metabolism ◽  
Receptor Membrane ◽  
Pleiotropic Functions

: Progesterone receptor membrane component 1 (PGRMC1) is a trans-membrane evolutionarily conserved protein with a cytochrome b5 like heme/steroid binding domain. PGRMC1 clinical levels are strongly suggested to correlate with poor patient survival and lung cancer prognosis. PGRMC1 has been reported to possess pleiotropic functions, such as participating in cellular and membrane trafficking, steroid hormone signaling, cholesterol metabolism and steroidogenesis, glycolysis and mitochondrial energy metabolism, heme transport and homeostasis, neuronal movement and synaptic function, autophagy, anti-apoptosis, stem cell survival and the list is still expanding. PGRMC1 mediates its pleiotropic functions through its ability to interact with multiple binding partners, such as epidermal growth factor receptor (EGFR), sterol regulatory element binding protein cleavage activating protein (SCAP), insulin induced gene-1 protein (Insig-1), heme binding proteins (hepcidin, ferrochelatase and cyp450 members), plasminogen activator inhibitor 1 RNA binding protein (PAIR-BP1). In this review, we provide a comprehensive overview of PGRMC1 and its associated pleiotropic functions that are indispensable for lung cancer promotion and progression, suggesting it as a prospective therapeutic target for intervention. Notably, we have compiled and reported various preclinical studies wherein prospective agonists and antagonists had been tested against PGRMC1 expressing cancer cell lines, suggesting it as a prospective therapeutic target for cancer intervention.

scholarly journals Musashi 2 influences chronic lymphocytic leukemia cell survival and growth making it a potential therapeutic target

Leukemia ◽  
2021 ◽  
Author(s):  
Florencia Palacios ◽  
Xiao-Jie Yan ◽  
Gerardo Ferrer ◽  
Shih-Shih Chen ◽  
Stefano Vergani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Chronic Lymphocytic Leukemia Cell ◽  
Hematopoietic Stem

AbstractProgression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation. While there is an established role for MSI2 in normal and malignant stem cells, much less is known about its expression and role in CLL. Here we report for the first time ex vivo and in vitro experiments that MSI2 protein levels are higher in dividing and recently divided leukemic cells and that downregulating MSI2 expression or blocking its function eliminates primary human and murine CLL and mature myeloid cells. Notably, mature T cells and hematopoietic stem and progenitor cells are not affected. We also confirm that higher MSI2 levels correlate with poor outcome markers, shorter time-to-first-treatment, and overall survival. Thus, our data highlight an important role for MSI2 in CLL-cell survival and proliferation and associate MSI2 with poor prognosis in CLL patients. Collectively, these findings pinpoint MSI2 as a potentially valuable therapeutic target in CLL.

scholarly journals Targeting of Non-Structural Protein 9 as a Novel Therapeutic Target for the Treatment of SARS-CoV-2

2020 ◽  
Vol 3 ◽  
Author(s):  
Matthew Anderson ◽  
John Turchi
Keyword(s):  
Viral Replication ◽  
Therapeutic Target ◽  
Rna Binding ◽  
Future Research ◽  
Great Promise ◽  
Dependent Manner ◽  
Nucleic Acid Binding ◽  
Structural Protein ◽  
Concentration Dependent Manner ◽  
Novel Therapeutic

Background/Hypothesis:  The 2019 novel coronavirus (SARS-CoV-2) is a human coronavirus responsible for a global pandemic with over 13 million confirmed cases. Currently, there are no treatments to block viral infection or replication. Exploring novel therapeutic targets for SARS-CoV-2 and future coronaviruses holds great promise for treating the current and future outbreaks. One such target is the non-structural protein 9 (nsp9), which has been shown to be highly conserved and unique to the coronavirus family as well as playing a role in viral replication. We hypothesize nsp9 is a viable target for therapeutic development.     Methods:  Towards determining the utility of targeting nsp9, a series of databases were queried for articles pertaining to nsp9 in SARS-CoV-2 and other coronaviruses and coronaviruses in general. We assessed structural, biochemical and cellular features of nsp9.      Results:  Nsp9 forms a homodimer via a conserved a-helix containing a glycine-rich interaction motif (GxxxG). Dimerization at the GxxxG interface is required for efficient viral replication. Nsp9’s core is an open, six-stranded b-barrel whose fold gives it a structure similar to nucleic acid binding OB-fold proteins. This OB-like fold has not been detected in replicative complexes of other RNA viruses and may reflect the unique and complex CoV replication machinery. Nsp9 is an indispensable component of the replication complex that binds single-stranded RNA in a concentration-dependent manner. A recent bioinformatic approach also found that nsp9 interacts with NF-kappa-B-repressing factor and may play a role in the IL-8/IL-6 mediated chemotaxis of neutrophils and inflammatory response observed in Covid-19 patients.     Conclusion/Potential Impact:   Based on this research, we conclude nsp9 represents a novel therapeutic target whose OB-like-fold may provide a targetable structure for interrupting RNA binding and impairing viral replication. This study will help inform current and future research that seeks to target nsp9’s structure and biochemical interactions as treatment for coronavirus infection. 

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