Ultrahigh-throughput discovery of modified aptamers as specific and potent enzyme inhibitors DOI Creative Commons
Claire Husser,

Janis Hoetzel,

Roger Cubì

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 16, 2024

Abstract Enzymes are instrumental to life and key actors of pathologies, making them relevant drug targets. Most enzyme inhibitors consist small molecules. Although efficient, their development is long, costly can come with unwanted off-targeting. Substantial gain in specificity discovery efficiency possible using biologicals. Best exemplified by antibodies, these drugs derived from living systems display high eased harnessing natural evolution. Aptamers nucleic acids sharing functional similarities antibodies while being deprived many limitations. Yet, the success rate inhibitory aptamer remained hampered lack an efficient pipeline. In this work, we addressed issue introducing ultrahigh-throughput strategy combining vitro selection, microfluidic screening bioinformatics. We demonstrate its discovering a modified that specifically strongly inhibits SPM-1, beta-lactamase recalcitrant potent inhibitors. Graphical

Язык: Английский

Near Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy DOI

Iris Flores,

Kathryn Monopoli,

Samuel Jackson

и другие.

Nucleic Acid Therapeutics, Год журнала: 2024, Номер 34(5), С. 234 - 244

Опубликована: Авг. 27, 2024

Small interfering RNAs (siRNAs) represent a novel class of drugs capable potent and sustained modulation genes across various tissues. Preclinical development siRNAs necessitates assessing efficacy toxicity in animal models. While identifying therapeutic leads with cross-species activity can expedite development, it may compromise be infeasible for certain gene targets. Here, we investigate whether deriving species-active from human-targeting leads-an approach termed mismatch conversion-can yield compounds. We systematically altered targeting human associated diseases-

Язык: Английский

Процитировано

1
Joining forces to develop individualized antisense oligonucleotides for patients with brain or eye diseases: the example of the Dutch Center for RNA Therapeutics DOI Creative Commons
Annemieke Aartsma‐Rus, Rob W.J. Collin, Ype Elgersma

и другие.

Therapeutic Advances in Rare Disease, Год журнала: 2024, Номер 5

Опубликована: Янв. 1, 2024

Antisense oligonucleotides (ASOs) offer versatile tools to modify the processing and expression levels of gene transcripts. As such, they have a high therapeutic potential for rare genetic diseases, where applicability each ASO ranges from thousands patients worldwide single individuals based on prevalence causative pathogenic variant. It was shown that development individualized ASOs feasible within an academic setting, starting with Milasen treatment patient CLN7 Batten’s disease in USA. Inspired by this, Dutch Center RNA Therapeutics (DCRT) established three medical centers Netherlands track record progressive, neurodegenerative, neurodevelopmental, retinal disorders. The goal DCRT is bundle expertise address national ethical, regulatory, financial issues related treatment, ultimately develop eligible diseases affecting central nervous system academic, not-for-profit setting. In this perspective, we describe establishment 2020 achievements so far, specific focus lessons learned: need processes procedures, global collaboration, raise awareness, fact N-of-1 N-of-a-few.

Язык: Английский

Процитировано

1
Hepatocyte targeting via the asialoglycoprotein receptor DOI Creative Commons
Fabricio Ramírez-Cortés, Petra Ménová

RSC Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 2, 2024

The asialoglycoprotein receptor (ASGPR) plays a crucial role in delivering therapeutics to hepatocytes. From nucleic acids LYTACs and drugs, we explore the current state-of-the-art strategies for hepatocyte targeting via ASGPR.

Язык: Английский

Процитировано

1
Why and How to Control P-Chirality in Phosphorothioated Therapeutic Oligonucleotides: Analytical Challenges Associated with Determination of Stereochemical Composition DOI

Tanja Poredoš,

Marko Trampuž,

Tjaša Gornik

и другие.

Organic Process Research & Development, Год журнала: 2024, Номер unknown

Опубликована: Дек. 6, 2024

Язык: Английский

Процитировано

1
Ultrahigh-throughput discovery of modified aptamers as specific and potent enzyme inhibitors DOI Creative Commons
Claire Husser,

Janis Hoetzel,

Roger Cubì

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 16, 2024

Abstract Enzymes are instrumental to life and key actors of pathologies, making them relevant drug targets. Most enzyme inhibitors consist small molecules. Although efficient, their development is long, costly can come with unwanted off-targeting. Substantial gain in specificity discovery efficiency possible using biologicals. Best exemplified by antibodies, these drugs derived from living systems display high eased harnessing natural evolution. Aptamers nucleic acids sharing functional similarities antibodies while being deprived many limitations. Yet, the success rate inhibitory aptamer remained hampered lack an efficient pipeline. In this work, we addressed issue introducing ultrahigh-throughput strategy combining vitro selection, microfluidic screening bioinformatics. We demonstrate its discovering a modified that specifically strongly inhibits SPM-1, beta-lactamase recalcitrant potent inhibitors. Graphical

Язык: Английский

Процитировано

0