scholarly journals Phosphorothioate modified oligonucleotide–protein interactions

2020 ◽  
Vol 48 (10) ◽  
pp. 5235-5253 ◽  
Author(s):  
Stanley T Crooke ◽  
Timothy A Vickers ◽  
Xue-hai Liang
Keyword(s):  
Protein Interactions ◽  
Antisense Oligonucleotides ◽  
Intracellular Trafficking ◽  
Recent Progress ◽  
Therapeutic Index ◽  
Pharmacological Properties ◽  
Detailed Understanding ◽  
Chemically Modified ◽  
Structure Activity ◽  
Modified Oligonucleotide

Abstract Antisense oligonucleotides (ASOs) interact with target RNAs via hybridization to modulate gene expression through different mechanisms. ASO therapeutics are chemically modified and include phosphorothioate (PS) backbone modifications and different ribose and base modifications to improve pharmacological properties. Modified PS ASOs display better binding affinity to the target RNAs and increased binding to proteins. Moreover, PS ASO protein interactions can affect many aspects of their performance, including distribution and tissue delivery, cellular uptake, intracellular trafficking, potency and toxicity. In this review, we summarize recent progress in understanding PS ASO protein interactions, highlighting the proteins with which PS ASOs interact, the influence of PS ASO protein interactions on ASO performance, and the structure activity relationships of PS ASO modification and protein interactions. A detailed understanding of these interactions can aid in the design of safer and more potent ASO drugs, as illustrated by recent findings that altering ASO chemical modifications dramatically improves therapeutic index.

scholarly journals Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2145
Author(s):  
Karen Rodríguez-Villar ◽  
Lilián Yépez-Mulia ◽  
Miguel Cortés-Gines ◽  
Jacobo David Aguilera-Perdomo ◽  
Edgar A. Quintana-Salazar ◽  
...  
Keyword(s):  
Phenyl Ring ◽  
Medicinal Chemistry ◽  
Structural Features ◽  
Pharmacological Properties ◽  
Antiprotozoal Activity ◽  
One Pot ◽  
Biological Assays ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Synthetic Methodologies

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.

N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases

2021 ◽  
Author(s):  
Erik A.L. Biessen ◽  
Theo J.C. Van Berkel
Keyword(s):  
Immune Responses ◽  
Targeted Delivery ◽  
Antisense Oligonucleotides ◽  
Sugar Metabolism ◽  
Innate Immune ◽  
Future Research ◽  
Clinical Use ◽  
Innate Immune Responses ◽  
Chemically Modified ◽  
Intrinsic Capacity

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9, at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.

Oligonucleotides carrying nucleoside antimetabolites as potential prodrugs

2021 ◽  
Vol 28 ◽  
Author(s):  
Carme Fàbrega ◽  
Anna Clua ◽  
Ramon Eritja ◽  
Anna Aviñó
Keyword(s):  
Antisense Oligonucleotides ◽  
Biomedical Applications ◽  
Enzymatic Degradation ◽  
Research Effort ◽  
Synergetic Effect ◽  
Chemotherapeutic Agents ◽  
Dna Nanostructures ◽  
Chemically Modified ◽  
Near Future ◽  
Large Research

Background: Nucleoside and nucleobase antimetabolites are an important class of chemotherapeutic agents for the treatment of cancer as well as other diseases. Introduction: In order to avoid undesirable side effects, several prodrug strategies have been developed for that purpose. In the present review, we describe a relatively unknown strategy that consists in the use of oligonucleotides modified with nucleoside antimetabolites as prodrugs. Method: The active nucleotides are generated by enzymatic degradation once incorporated into cells. This strategy has attracted large interest and is very active at present due to the continuous developments made on therapeutic oligonucleotides and the recent advances in the field of nanomaterials and nanomedicine. Results: A large research effort was done mainly in the improvement of the antiproliferative properties of nucleoside homopolymers, but recently, chemically modified aptamers, antisense oligonucleotides and/or siRNA carrying antiproliferative nucleotides have demonstrated a great potential due to the synergetic effect of both therapeutic entities. In addition, DNA nanostructures with interesting properties have been built to combine antimetabolites and enhancers of cellular uptake in the same scaffold. Finally, protein nanoparticles functionalized with receptor-binders and antiproliferative oligomers represent a new avenue for a more effective treatment in cancer therapy. Conclusion: It is expected that oligonucleotides carrying nucleoside antimetabolites will be considered as potential drugs in the near future for biomedical applications.

scholarly journals Diversity Focused Semisyntheses of Tetronate Polyether Ionophores

2019 ◽  
Author(s):  
Shaoquan Lin ◽  
Han Liu ◽  
Esben B. Svenningsen ◽  
Christine Pedersen ◽  
Peter Nørby ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Cancer Cells ◽  
Mammalian Cells ◽  
Biological Activities ◽  
Structural Diversity ◽  
Bacterial Activity ◽  
Cation Binding ◽  
Detailed Understanding ◽  
Structure Activity ◽  
Aggressive Cancer

The polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many family members possess highly potent antimicrobial activity and a few selected compounds have ability to target particularly aggressive cancer cells. Despite these interesting perspectives, a detailed understanding of the cellular mode-of-action of polyether ionophores is generally lacking. In principle, broad mapping of structure-activity relationships across several biological activities could provide mechanistic insights as well as identification of lead structures but access to structural diversity within the overall class is synthetically very challenging. In this manuscript, we demonstrate that novel polyether ionophores can be constructed by recycling components of highly abundant polyethers. We provide the first examples of synthetically incorporating halogen-functionalized tetronic acids as cation-binding groups into polyether ionophores and we identify analogs with strong anti-bacterial activity and minimal effects on mammalian cells.

Recent Progress in Methylation of (Hetero)Arenes by Cross-Coupling or C–H Activation

Synlett ◽  
2018 ◽  
Vol 29 (04) ◽  
pp. 375-382 ◽  
Author(s):  
Yahu Liu ◽  
Xuebin Liao ◽  
Lu Hu
Keyword(s):  
Recent Progress ◽  
Cross Coupling ◽  
Structure Activity Relationship ◽  
Biological Properties ◽  
Aryl Halides ◽  
Lead Optimization ◽  
Activity Relationship ◽  
Research Groups ◽  
Structure Activity ◽  
Methyl Effect

Owing to the ‘magic methyl effect’ on a compound’s physical and biological properties, methylation is a strategy frequently used by medicinal chemists in structure–activity relationship studies or in lead optimization. This article highlights the most recent reported methods for the direct methylation of (hetero)arenes, which mainly involve either C–H functionalization or cross-coupling of methylating reagents with (hetero)aryl halides. Methylation of C–H bonds of (hetero)-arenes, which is atom economical, has been explored by several research groups in recent years. Given the unmatchable availability of (hetero)aryl halides, we believe that Ni-catalyzed methylation using iodomethane or deuterated iodomethane as the methyl source is one of the most convenient methods.

scholarly journals Understanding the effect of controlling phosphorothioate chirality in the DNA gap on the potency and safety of gapmer antisense oligonucleotides

2020 ◽  
Vol 48 (4) ◽  
pp. 1691-1700 ◽  
Author(s):  
Michael E Østergaard ◽  
Cheryl L De Hoyos ◽  
W Brad Wan ◽  
Wen Shen ◽  
Audrey Low ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Therapeutic Index ◽  
Rna Cleavage ◽  
Systematic Analysis ◽  
Phosphodiester Backbone ◽  
High Affinity ◽  
Backbone Modification ◽  
Therapeutic Profile ◽  
In Cells

Abstract Therapeutic oligonucleotides are often modified using the phosphorothioate (PS) backbone modification which enhances stability from nuclease mediated degradation. However, substituting oxygen in the phosphodiester backbone with sulfur introduce chirality into the backbone such that a full PS 16-mer oligonucleotide is comprised of 215 distinct stereoisomers. As a result, the role of PS chirality on the performance of antisense oligonucleotides (ASOs) has been a subject of debate for over two decades. We carried out a systematic analysis to determine if controlling PS chirality in the DNA gap region can enhance the potency and safety of gapmer ASOs modified with high-affinity constrained Ethyl (cEt) nucleotides in the flanks. As part of this effort, we examined the effect of systematically controlling PS chirality on RNase H1 cleavage patterns, protein mislocalization phenotypes, activity and toxicity in cells and in mice. We found that while controlling PS chirality can dramatically modulate interactions with RNase H1 as evidenced by changes in RNA cleavage patterns, these were insufficient to improve the overall therapeutic profile. We also found that controlling PS chirality of only two PS linkages in the DNA gap was sufficient to modulate RNase H1 cleavage patterns and combining these designs with simple modifications such as 2′-OMe to the DNA gap resulted in dramatic improvements in therapeutic index. However, we were unable to demonstrate improved potency relative to the stereorandom parent ASO or improved safety over the 2′-OMe gap-modified stereorandom parent ASO. Overall, our work shows that while controlling PS chirality can modulate RNase H1 cleavage patterns, ASO sequence and design are the primary drivers which determine the pharmacological and toxicological properties of gapmer ASOs.

Dietary Migraine: Recent Progress in the Red (And White) Wine Story

Cephalalgia ◽  
1995 ◽  
Vol 15 (2) ◽  
pp. 101-103 ◽  
Author(s):  
M Sandler ◽  
N-Y Li ◽  
N Jarrett ◽  
V Glover
Keyword(s):  
Recent Progress ◽  
Red Wine ◽  
White Wine ◽  
Clinical Entity ◽  
Pharmacological Properties ◽  
Sequence Of Events ◽  
Objective Evidence ◽  
Migrainous Headache

The concept of dietary migraine as a clinical entity remains controversial. We review here such objective evidence that has been put forward for its existence. Red wine, in particular, is commonly alleged to initiate attacks in susceptible individuals. We discuss how some of its recently described pharmacological properties might trigger off the sequence of events leading to migrainous headache.

scholarly journals Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 817
Author(s):  
Tsuyoshi Yamamoto ◽  
Yahiro Mukai ◽  
Fumito Wada ◽  
Chisato Terada ◽  
Yukina Kayaba ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Ex Vivo ◽  
The Body ◽  
Locked Nucleic Acid ◽  
Imaging Studies ◽  
Phosphodiester Bond ◽  
Chemically Modified ◽  
Ex Vivo Imaging ◽  
Mirna Targeting

The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy.

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