scholarly journals Photoswitches for controllable RNA binding: A future approach in the RNA-targeting therapy

2021 ◽  
Author(s):  
Daria V. Berdnikova
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Rna Binding ◽  
Genetic Diseases ◽  
Targeting Therapy ◽  
Rna Targeting

RNA is an emerging drug target that opens new perspectives in the treatment of viral and bacterial infections, cancer and a range of so far incurable genetic diseases. Among the...

scholarly journals RNA-targeting Therapy: A Promising Approach to Reach Non-Druggable Targets

2021 ◽  
Vol 14 (4) ◽  
pp. 1781-1790
Author(s):  
Dalia Zaafar ◽  
Toka Elemary ◽  
Yara Abdel Hady ◽  
Aya Essawy
Keyword(s):  
Antisense Oligonucleotides ◽  
New Technologies ◽  
Genetic Diseases ◽  
Disease Diagnosis ◽  
Targeting Therapy ◽  
Specific Targeting ◽  
Modern Drug ◽  
Rna Targeting ◽  
Druggable Targets ◽  
Promising Type

The term "non-druggable" refers to a protein that cannot be targeted pharmacologically; recently, significant efforts have been made to convert these proteins into targets that are reachable or "druggable." Pharmacologically targeting these difficult proteins has emerged as a major challenge in modern drug development, necessitating the innovation and development of new technologies. The idea of using RNA-targeting therapeutics as a platform to reach unreachable targets is very appealing. Antisense oligonucleotides, nucleic acid or aptamers, RNA interference therapeutics, microRNA, and synthetic RNA are examples of RNA-targeting therapeutics. Many of these agents were FDA-approved for the treatment of rare or genetic diseases, as well as molecular markers for disease diagnosis. As a promising type of therapeutic, many studies are being conducted in order for more and more of them to be approved and used in different disease treatments and to shift them from treating rare diseases only to being used as more specific targeting agents in the treatment of various common diseases. This article will look at some of the most recent technological and pharmaceutical advances that have contributed to the erosion of the concept of undruggability.

Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

2020 ◽  
Vol 21 (10) ◽  
pp. 1011-1026
Author(s):  
Bruna O. Costa ◽  
Marlon H. Cardoso ◽  
Octávio L. Franco
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Specific Chemical ◽  
Target Interaction ◽  
Multiresistant Bacteria ◽  
Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

Bacterial Polyphosphate Kinases Revisited: Role in Pathogenesis and Therapeutic Potential

2019 ◽  
Vol 20 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Lalit Kumar Gautam ◽  
Prince Sharma ◽  
Neena Capalash
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Wide Distribution ◽  
Medical Community ◽  
Polyphosphate Kinase ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Resistant Strains ◽  
Structural Aspects

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.

scholarly journals Roles of Splicing Factors in Hormone-Related Cancer Progression

2020 ◽  
Vol 21 (5) ◽  
pp. 1551 ◽  
Author(s):  
Toshihiko Takeiwa ◽  
Yuichi Mitobe ◽  
Kazuhiro Ikeda ◽  
Kuniko Horie-Inoue ◽  
Satoshi Inoue
Keyword(s):  
Cancer Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Isoforms ◽  
Targeting Therapy ◽  
Biological Phenomena ◽  
New Strategy ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Prostate Cancers ◽  
Mrna Precursor

Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are involved in various aspects of cancers such as proliferation, migration and response to hormones, suggesting that splicing-targeting therapy can be promising as a new strategy for cancer treatment. In this review, we focus on the splicing regulation by RNA-binding proteins including Drosophila behavior/human splicing (DBHS) family proteins, serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in hormone-related cancers, such as breast and prostate cancers.

scholarly journals Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy

RNA Biology ◽  
2015 ◽  
Vol 12 (4) ◽  
pp. 412-425 ◽  
Author(s):  
Lukas J Aaldering ◽  
Hossam Tayeb ◽  
Shilpa Krishnan ◽  
Susan Fletcher ◽  
Stephen D Wilton ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Tissue Specific ◽  
Targeting Therapy ◽  
Rna Targeting

scholarly journals Small Molecule-Inducible RNA-Targeting Systems for Temporal Control of RNA Regulation

2020 ◽  
Author(s):  
Simone Rauch ◽  
Krysten A. Jones ◽  
Bryan Dickinson
Keyword(s):  
Gene Expression ◽  
Small Molecule ◽  
Rna Binding ◽  
Effector Proteins ◽  
Dependent Manner ◽  
Rna Regulation ◽  
Biosensor System ◽  
Gene Expression Control ◽  
Rna Targeting ◽  
Target Transcript

<div>All aspects of mRNA lifetime and function, including its stability, translational to protein, and trafficking through the cell, are tightly regulated through coordinated post-transcriptional modifications and interactions with a multitude of effector proteins. Despite the increasing recognition of RNA regulation as a critical layer of mammalian gene expression control and its increasing excitement as a therapeutic target, tools to study and control RNA regulatory mechanisms with temporal precision in their endogenous environment are lacking. Here, we present small molecule-inducible RNA-targeting effectors based on our previously-developed CRISPR/Cas-inspired RNA targeting system (CIRTS). The CIRTS biosensor system is based on guide RNA (gRNA)-dependent RNA binding domains that interact with a target transcript using Watson-Crick-Franklin base pair interactions. Addition of a small molecule recruits an RNA effector to the target transcript, thereby eliciting a local effect on the transcript. In this work, we showcase that these CIRTS biosensors can trigger inducible RNA editing, degradation, or translation on target transcripts in a small molecule-dependent manner. We further go on to show that the new CIRTS editor can induce RNA base editing in a small molecule-dependent manner in vivo. Collectively this work provides a useful new set of tools to probe the dynamics of RNA regulatory systems and a new approach to control gene expression at the RNA level.</div>

scholarly journals Type III CRISPR-Cas systems generate cyclic oligoadenylate second messengers to activate Csm6 RNases

2017 ◽  
Author(s):  
Ole Niewoehner ◽  
Carmela Garcia-Doval ◽  
Jakob T. Rostøl ◽  
Christian Berk ◽  
Frank Schwede ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Rna Binding ◽  
Second Messengers ◽  
Allosteric Activation ◽  
Conceptual Similarity ◽  
Type Iii ◽  
Rna Transcripts ◽  
Rna Targeting ◽  
Target Rna

ABSTRACTIn many prokaryotes, type III CRISPR–Cas systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex that possesses dual RNase and DNase activities. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone ribonuclease that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the type III interference complex, the Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CARF domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to a hitherto unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

RNA targeting through binding of small molecules: Studies on t-RNA binding by the cytotoxic protoberberine alkaloidcoralyne

2009 ◽  
Vol 5 (3) ◽  
pp. 244-254 ◽  
Author(s):  
Md. Maidul Islam ◽  
Prateek Pandya ◽  
Surat Kumar ◽  
Gopinatha Suresh Kumar
Keyword(s):  
Small Molecules ◽  
Rna Binding ◽  
Rna Targeting

scholarly journals Small Molecule-Inducible RNA-Targeting Systems for Temporal Control of RNA Regulation

2020 ◽  
Author(s):  
Simone Rauch ◽  
Krysten A. Jones ◽  
Bryan Dickinson
Keyword(s):  
Gene Expression ◽  
Small Molecule ◽  
Rna Binding ◽  
Effector Proteins ◽  
Dependent Manner ◽  
Rna Regulation ◽  
Biosensor System ◽  
Gene Expression Control ◽  
Rna Targeting ◽  
Target Transcript

<div>All aspects of mRNA lifetime and function, including its stability, translational to protein, and trafficking through the cell, are tightly regulated through coordinated post-transcriptional modifications and interactions with a multitude of effector proteins. Despite the increasing recognition of RNA regulation as a critical layer of mammalian gene expression control and its increasing excitement as a therapeutic target, tools to study and control RNA regulatory mechanisms with temporal precision in their endogenous environment are lacking. Here, we present small molecule-inducible RNA-targeting effectors based on our previously-developed CRISPR/Cas-inspired RNA targeting system (CIRTS). The CIRTS biosensor system is based on guide RNA (gRNA)-dependent RNA binding domains that interact with a target transcript using Watson-Crick-Franklin base pair interactions. Addition of a small molecule recruits an RNA effector to the target transcript, thereby eliciting a local effect on the transcript. In this work, we showcase that these CIRTS biosensors can trigger inducible RNA editing, degradation, or translation on target transcripts in a small molecule-dependent manner. We further go on to show that the new CIRTS editor can induce RNA base editing in a small molecule-dependent manner in vivo. Collectively this work provides a useful new set of tools to probe the dynamics of RNA regulatory systems and a new approach to control gene expression at the RNA level.</div>

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