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PDA Journal of Pharmaceutical Science... 2023All starting materials and the active pharmaceutical ingredient (API) of a drug product must be subjected to analytical identity (ID) testing as part of the release...
All starting materials and the active pharmaceutical ingredient (API) of a drug product must be subjected to analytical identity (ID) testing as part of the release prior to their introduction into the pharmaceutical manufacturing process. Generally, it is preferable for Quality Control (QC) laboratories to perform ID tests using a simple and fast to perform, yet highly specific, analytical method. This preference also applies to oligonucleotides, an emerging class of APIs, where a combined ID testing strategy should be applied, including intact mass determination and a sequence-specific method. Within this work, we investigated whether ultravioloet (UV)-spectrometric determination of the melting temperature (T) of oligonucleotides is a suitable sequence-specific ID test for these substances in the pharmaceutical routine QC. Therefore, this method was evaluated for its specificity toward deviating oligonucleotide sequences. For this, model oligonucleotide sequences and variants thereof were designed, synthesized, and analyzed, resulting in precise and specific data. Even single base exchanges or single nucleotide deletions and insertions in the sequences led to significant changes in the measured T of the corresponding oligonucleotide duplexes. These results indicate a generally high specificity of the method toward subtle changes in oligonucleotide sequences and confirm the applicability of the analytical method as part of the ID testing strategy for oligonucleotides in the pharmaceutical QC environment.
Topics: Oligonucleotides; Temperature; Pharmaceutical Preparations
PubMed: 36122915
DOI: 10.5731/pdajpst.2021.012694 -
Methods in Molecular Biology (Clifton,... 2022Libraries of DNA-encoded compounds (DELs) are a validated screening technology for drug discovery. Here we describe a library synthesis strategy that starts with a solid...
Libraries of DNA-encoded compounds (DELs) are a validated screening technology for drug discovery. Here we describe a library synthesis strategy that starts with a solid phase-bound, chemically very stable hexathymidine DNA sequence "hexT." Different heterocycle conjugates of the hexT oligonucleotide were synthesized from simple starting materials using metal or acid catalysts. The hexT conjugates were isolated, characterized, and ligated to coding DNA sequences.
Topics: Combinatorial Chemistry Techniques; DNA; Drug Discovery; Gene Library; Oligonucleotides; Small Molecule Libraries
PubMed: 36083549
DOI: 10.1007/978-1-0716-2545-3_14 -
Ciba Foundation Symposium 1997The medicinal chemistry effort directed toward improving antisense and antigene oligonucleotides has synthesized a large number of phosphate, ribose and heterocyclic... (Review)
Review
The medicinal chemistry effort directed toward improving antisense and antigene oligonucleotides has synthesized a large number of phosphate, ribose and heterocyclic base analogues. The phosphorothioate linkage is currently still the analogue linkage of choice for antisense studies. This is despite many years of effort to find alternatives that overcome the limitations of phosphorothioates. A number of modifications to phosphate and ribose have resulted in enhanced binding to RNA as measured by Tm, but generally the biological effects have been less dramatic. Currently, the most potent oligonucleotides have capitalized on recruiting the cellular enzyme RNase H to perform sequence-specific destruction of a targeted RNA. Virtually all modifications to phosphate or ribose other than phosphorothioate result in the loss of this recruitment. Chimeric strategies have overcome this limitation. Affinity and potency can additionally be improved by modifying the Watson-Crick-pairing heterocycles. Recent years have brought much consensus in terms of the mechanism of action of antisense oligonucleotides. A controversial area is the ability of oligonucleotides to permeate cells in whole animals. This issue will determine if antisense and triple helix technology results in practical broad-based therapeutics.
Topics: Animals; Humans; Oligonucleotides
PubMed: 9383565
DOI: No ID Found -
Current Opinion in Investigational... Jun 2008Aegera, under license from Idera Pharmaceuticals, is developing AEG-35156, a 19-mer phosphorothioate antisense oligonucleotide targeting the caspase inhibitor X-linked... (Review)
Review
Aegera, under license from Idera Pharmaceuticals, is developing AEG-35156, a 19-mer phosphorothioate antisense oligonucleotide targeting the caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) messenger RNA, for the potential treatment of cancer. Several clinical trials are ongoing and include: two phase I monotherapy clinical trials for the potential treatment of cancer and in patients with solid tumors; a phase I combination clinical trial of AEG-35156 with docetaxel in locally advanced, metastatic, or recurrent solid tumors; four phase I/II combination clinical trials for the potential treatment of pancreatic cancer, advanced breast cancer, advanced NSCLC, and acute myeloid leukemia. Mild to moderate adverse effects were observed in early phase clinical trials. Aegera plans to initiate randomized phase III trials if tolerable side effects and evidence of activity are demonstrated in phase I/II clinical trials.
Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Drug Evaluation, Preclinical; Humans; Neoplasms; Oligonucleotides; Oligonucleotides, Antisense; Patents as Topic; Randomized Controlled Trials as Topic; Structure-Activity Relationship; X-Linked Inhibitor of Apoptosis Protein
PubMed: 18516763
DOI: No ID Found -
Current Pharmaceutical Design 2008
Topics: Drug Delivery Systems; Drug Evaluation, Preclinical; Oligonucleotides; RNA Interference
PubMed: 19075736
DOI: 10.2174/138161208786898824 -
Nihon Rinsho. Japanese Journal of... Nov 2012
Topics: Animals; Aptamers, Nucleotide; Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 23513872
DOI: No ID Found -
Current Opinion in Biotechnology Apr 2001
Review
Topics: Gene Targeting; Genes, Plant; Nuclear Proteins; Oligonucleotides
PubMed: 11287232
DOI: 10.1016/s0958-1669(00)00194-4 -
Nucleic Acid Therapeutics Aug 2020The most common approach for the manufacture of oligonucleotides includes isolation of the active pharmaceutical ingredient (API) via lyophilization to provide a solid...
The most common approach for the manufacture of oligonucleotides includes isolation of the active pharmaceutical ingredient (API) via lyophilization to provide a solid product, which is then dissolved to provide an aqueous formulation. It is well known from the development and manufacture of large molecules ("biologics") that API production does not always require isolation of solid API before drug product formulation, and this article provides technical considerations for the analogous use of oligonucleotide API in solution. The primary factor considered is solution stability, and additional factors such as viscosity, concentration, end-to-end manufacturing, microbiological control, packaging, and storage are also discussed. The technical considerations discussed in this article will aid the careful evaluation of the relative advantages and disadvantages of solution versus powder API for a given oligonucleotide drug substance.
Topics: Chemistry, Pharmaceutical; Freeze Drying; Humans; Oligonucleotides; Solutions
PubMed: 32379529
DOI: 10.1089/nat.2020.0846 -
Current Medicinal Chemistry 2005In this account we summarise recent studies on oligonucleotides and oligonucleotide derivatives and their utilisation in antigene, antisense and decoy approaches, with... (Review)
Review
In this account we summarise recent studies on oligonucleotides and oligonucleotide derivatives and their utilisation in antigene, antisense and decoy approaches, with particular attention to peptide nucleic acids, locked nucleic acids and oligonucleotide conjugates, the most promising compounds in this field.
Topics: Antineoplastic Protocols; Cross-Linking Reagents; Humans; Molecular Conformation; Neoplasms; Nucleic Acids; Oligonucleotides; Oligonucleotides, Antisense
PubMed: 15638731
DOI: 10.2174/0929867053363603 -
Advanced Drug Delivery Reviews Jun 2015
Topics: Biotechnology; Drug Discovery; Oligonucleotides
PubMed: 26175452
DOI: 10.1016/j.addr.2015.06.010