ABSTRACT
All widely used mRNA vaccines against COVID-19 contain in their sequence 1-methylpseudouridine (m1Ψ) instead of uridine. In this publication, we report two high resolution crystal structures (at up to 1.01 and 1.32â Å, respectively) of one such double-stranded 12-mer RNA sequence crystallized in two crystal forms. The structures are compared with similar structures which do not contain this modification. Additionally, the X-ray structure of 1-methyl-pseudouridine itself was determined.
Subject(s)
Pseudouridine , Pseudouridine/analogs & derivatives , RNA , Humans , Pseudouridine/chemistry , mRNA Vaccines , COVID-19 VaccinesABSTRACT
A new test was elaborated to identify a new set of orthogonal protecting groups. With the developed method eight different protecting groups were tested under various deprotection conditions and the complex reaction mixtures were analysed by HPLC. The developed method allows for quick identification of orthogonality using simple model structures.
Subject(s)
Biological Products/chemistry , Chromatography, High Pressure Liquid/methods , Glucosides/chemistry , Biological Products/chemical synthesis , Glucosides/chemical synthesis , Molecular ConformationABSTRACT
Academic drug discovery is playing an increasingly important role in the identification of new therapies for a wide range of diseases. There is no one model that guarantees success. We describe here a drug discovery story where chance, the ability to capitalise on chance, and the assembling of a range of expertise, have all played important roles in the discovery and subsequent development of an antibiotic chemotype based on the bis-benzimidazole scaffold, with potency against a number of current therapeutically challenging diseases. One compound in this class, SMT19969, has recently entered Phase 2 human clinical trials for the treatment of Clostridium difficile infections.
ABSTRACT
Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.
Subject(s)
Drug Discovery , Indazoles/chemical synthesis , Microsomes, Liver/drug effects , Triazoles/chemical synthesis , Dose-Response Relationship, Drug , Humans , Indazoles/chemistry , Indazoles/therapeutic use , Molecular Structure , Muscular Dystrophy, Duchenne/drug therapy , Solubility , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/therapeutic useABSTRACT
A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.
