A5030201383- RNA Research and Splicing
- Antimicrobial Peptides and Activities
- RNA and protein synthesis mechanisms
- Antifungal resistance and susceptibility
- Antimicrobial agents and applications
- Genetic Neurodegenerative Diseases
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Viral Infections and Immunology Research
- Polydiacetylene-based materials and applications
- Advanced biosensing and bioanalysis techniques
- Neurogenetic and Muscular Disorders Research
- MicroRNA in disease regulation
- Fungal Infections and Studies
- Advanced Fluorescence Microscopy Techniques
- Cancer therapeutics and mechanisms
- Carbohydrate Chemistry and Synthesis
- Pediatric health and respiratory diseases
- Mitochondrial Function and Pathology
- Amyotrophic Lateral Sclerosis Research
- Synthesis and Biological Evaluation
- Dendrimers and Hyperbranched Polymers
- Antimicrobial Resistance in Staphylococcus
- Nanoplatforms for cancer theranostics
- Microbial Natural Products and Biosynthesis
Hebrew University of Jerusalem
2022-2025
Scripps Research Institute
2019-2023
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023
Tel Aviv University
2015-2021
Exact Sciences (United States)
2016
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...
Fungal-bacterial interactions generate unique biofilms that cause many infections in humans. Candida albicans interact with Streptococcus mutans dental associated severe childhood tooth-decay, a prevalent pediatric oral disease. Current modalities are ineffective and primarily based on antimicrobial monotherapies despite the polymicrobial nature of infection. Here, we show combination clinically used topical antifungal fluconazole povidone iodine (PI) can completely suppress C. carriage...
Reprogramming known medicines for a novel target with activity and selectivity over the canonical is challenging. By studying binding interactions between RNA folds small-molecule mining resultant dataset across human RNAs, we identified that Dovitinib, receptor tyrosine kinase (RTK) inhibitor, binds precursor to microRNA-21 (pre-miR-21). Dovitinib was rationally reprogrammed pre-miR-21 by using it as an recognition element in chimeric compound also recruits RNase L induce RNA's catalytic...
Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting RNA repeat expansion.
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...
Azoles are the most commonly used class of antifungal drugs, yet where they localize within fungal cells and how imported remain poorly understood. Azole antifungals target lanosterol 14α-demethylase, a cytochrome P450, encoded by ERG11 in Candida albicans, prevalent pathogen. We report synthesis fluorescent probes that permit visualization azoles live cells. Probe 1 is dansyl dye-conjugated azole, probe 2 Cy5-conjugated azole. Docking computations indicated each can occupy active site P450....
Antimicrobial resistance within a wide range of pathogenic bacteria is an increasingly serious threat to global public health. Among these are the highly resistant, versatile and possibly aggressive bacteria, Staphylococcus aureus. Lincosamide antibiotics were proved be effective against this pathogen. This small, albeit important group mostly active Gram-positive but also used selected Gram-negative anaerobes protozoa. S. aureus lincosamides can acquired by modifications and/or mutations in...
MicroRNAs (miRs) have been implicated in numerous diseases, presenting an attractive target for the development of novel therapeutics. The various regulatory roles miRs cellular processes underscore need precise strategies. Recent advances RNA research offer hope by enabling identification small molecules capable selectively targeting specific disease-associated miRs. This understanding paves way developing that can modulate activity Herein, we discuss progress made field drug discovery...
The increasing emergence of drug-resistant fungal pathogens, together with the limited number available antifungal drugs, presents serious clinical challenges to treating systemic, life-threatening infections. Repurposing existing drugs augment activity well-tolerated antifungals is a promising strategy potential be implemented rapidly. Here, we explored mechanism by which colistin, positively charged lipopeptide antibiotic, enhances fluconazole, most widely used orally antifungal. In range...
Abstract The effect of di‐ N ‐methylation bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di‐ cationic amphiphiles several diversely structured AGs resulted in a significant increase hydrophobicity compared to the parent compounds that improved their interactions with lipids. modification led an enhancement antibacterial and broader spectrum. While were either modestly active or inactive against Gram‐negative pathogens, corresponding...
Abstract Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo‐oligosaccharide antibiotics interfere with the structure and function of bacterial membranes offer a promising direction for development novel antibiotics. Herein, we report design synthesis pseudo‐trisaccharide tobramycin its pseudo‐disaccharide segment nebramine. activity, membrane selectivity, mode action, structure–activity relationships were studied. Several showed marked antimicrobial one amphiphilic...
Antimicrobial cationic amphiphiles derived from aminoglycosides act through cell membrane permeabilization but have limited selectivity for microbial membranes. Herein, we report that an increased degree of unsaturation in the fatty acid segment antifungal aminoglycoside tobramycin significantly reduced toxicity to mammalian cells. A collection tobramycin-derived substituted with C18 lipid chains varying and double bond configuration were synthesized. All had potent activity against a panel...
Abstract A critical aspect of drug design is optimal target inhibition by specifically delivering the molecule not only to tissue or cell but also its therapeutically active site within cell. This study demonstrates, as a proof principle, that efficacy can be increased considerably structural modification targets it relevant organelle. Specifically, varying fluorescent dye segment an antifungal azole was directed from fungal mitochondria endoplasmic reticulum (ER), organelle harbors target....
A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is most common genetic cause amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from expansion, r(G 4 C 2 ) exp , causes various pathologies, including retention, aberrant translation that produces toxic dipeptide proteins (DPRs), sequestration RNA-binding (RBPs) foci. Here, we describe a small molecule potently selectively interacts with mitigates disease pathologies spinal neurons...
In fungal cells, the endoplasmic reticulum (ER) harbors several of enzymes involved in biosynthesis ergosterol, an essential membrane component, making this organelle site action antifungal azole drugs, used as a first-line treatment for infections. This highlights need specific fluorescent labeling cells pathogenic fungi. Here we report on development and evaluation collection ER trackers panel Candida, considered most frequently encountered pathogen These enabled imaging live cells....
Abstract Cationic amphiphiles are a large and diverse class of antimicrobial agents. Although their mode action is not fully resolved, it generally accepted that these antimicrobials perturb the structural integrity plasma membrane leading to microbial cell disruption. Here we report on development inherently fluorescent antifungal cationic study effects cells Candida , one most common fungal pathogens in humans. Fluorescent images yeast express reporter protein revealed rapidly accumulated...
Myotonic dystrophy type 2 (DM2) is a genetically defined muscular that caused by an expanded repeat of r(CCUG) [r(CCUG)
Herein we report that an imidazole-decorated cationic amphiphile derived from the pseudo-disaccharide nebramine has potent antifungal activity against strains of Candida glabrata pathogens. In combination with natural bis-benzylisoquinoline alkaloid tetrandrine reported demonstrated synergistic albicans This unique membrane disruptor caused no detectible mammalian red blood cell hemolysis at concentrations up to more than two orders magnitude greater its minimal inhibitory tested C. strains....
Several important antimicrobial drugs act by permeabilizing cell membranes. In this study, we showed that the intensity of membrane permeability caused cationic amphiphiles can be modified not only their concentration but also through light-induced isomerization lipid segment. Two types photo-isomerizable were developed and effects photo-isomerization on bacterial growth evaluated. One photo-isomer inhibited division, whereas other led to a rapid lethal membrane-disrupting effect. The switch...