A5012039351- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Bioactive Compounds and Antitumor Agents
- Invertebrate Taxonomy and Ecology
- Study of Mite Species
- Microbial Natural Products and Biosynthesis
- Viral Infections and Immunology Research
- SARS-CoV-2 and COVID-19 Research
- Molecular Biology Techniques and Applications
- interferon and immune responses
- Protein Degradation and Inhibitors
Scripps Research Institute
2019-2023
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023
Scripps (United States)
2023
COVID-19 is a global pandemic, thus requiring multiple strategies to develop modalities against it. Herein, we designed bioactive small molecules that target functional structure within the SARS-CoV-2's RNA genome, causative agent of COVID-19. An analysis characterize genome provided revised model SARS-CoV-2 frameshifting element, in particular its attenuator hairpin. By studying an RNA-focused molecule collection, identified drug-like (C5) avidly binds hairpin with Kd 11 nM. The compound...
Abstract Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding molecular recognition of RNA structures small molecules. Here we studied patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded structures. Mapping these interaction landscapes across human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind...
Significance The development of selective bioactive compounds that target RNA structures is difficult. Here we report an approach to identify low molecular weight fragments bind a cancer-causing RNA. By determining where the within target, they can be assembled provide high-affinity and potent inhibitor. This could general way develop small molecules RNA, which previously was considered “undruggable.” It applied precision lead medicine against contributes cancer metastasis.
Significance Drug discovery generally investigates one target at a time, in sharp contrast to living organisms, which mold ligands and targets by evolution of highly complex molecular interaction networks. We recapitulate this modality encoding drug structures DNA, allowing the entire DNA-encoded library interact with thousands RNA fold targets, then decoding both sequencing. This information serves as filter identify human RNAs aberrantly produced cancer that are also binding partners...
The interactions between cellular RNAs in MDA-MB-231 triple negative breast cancer cells and a panel of small molecules appended with diazirine cross-linking moiety an alkyne tag were probed transcriptome-wide live cells. allows for facile pull-down bound by each molecule, the enrichment RNA target defines compound's molecular footprint. Among 34 chemically diverse studied, six enriched RNAs. most highly interaction occurs novel RNA-binding compound F1 structured region 5′ untranslated...
RNA is challenging to target with bioactive small molecules, particularly those of low molecular weight that bind sufficient affinity and specificity. In this report, we developed a platform address challenge, affording novel interaction. An RNA-focused small-molecule fragment collection (n = 2500) was constructed by analyzing features in all publicly reported compounds RNA, the largest fragments date. The RNA-binding landscape for each studied using library-versus-library selection an...
Small molecules that target RNA and effect their cleavage are useful chemical probes potential lead medicines. In this study, we investigate factors affecting degradation of two cancer-associated targets, the mRNA encodes transcription factor JUN (c-Jun) hairpin precursor to microRNA-372 (pre-miR-372). The targets harbor same small-molecule binding site juxtaposed with different neighboring structures. Specifically, pre-miR-372 has AU pairs contiguous purines on one strand near site, making...
The discovery of biofunctional natural products (NPs) has relied on the phenotypic screening extracts and subsequent laborious work to dereplicate active NPs define cellular targets. Herein, present as crude extracts, partially purified fractions, pure compounds were screened directly against molecular target libraries RNA structural motifs in a library-versus-library fashion. We identified 21 hits with affinity for RNA, including one NP, nocathiacin I (NOC-I). resultant data set NOC-I-RNA...
Although fragment-based drug discovery (FBDD) has been successfully implemented and well-explored for protein targets, its feasibility RNA targets is emerging. Despite the challenges associate with selective targeting of RNA, efforts to integrate known methods binder approaches fruitful, as a few bioactive ligands have identified. Here, we review various provide insight into experimental design outcomes, guide future work in area. Indeed, investigations surrounding molecular recognition by...