11 research outputs found
Proximity-Induced Nucleic Acid Degrader (PINAD) approach to targeted RNA degradation using small molecules
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.info:eu-repo/semantics/publishedVersio
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Machine Learning Uncovers Natural Product Modulators of the 5-Lipoxygenase Pathway and Facilitates the Elucidation of Their Biological Mechanisms.
Machine learning (ML) models have made inroads into chemical sciences, with optimization of chemical reactions and prediction of biologically active molecules being prime examples thereof. These models excel where physical experiments are expensive or time-consuming, for example, due to large scales or the need for materials that are difficult to obtain. Studies of natural products suffer from these issues─this class of small molecules is known for its wealth of structural diversity and wide-ranging biological activities, but their investigation is hindered by poor synthetic accessibility and lack of scalability. To facilitate the evaluation of these molecules, we designed ML models that predict which natural products can interact with a particular target or a relevant pathway. Here, we focused on discovering natural products that are capable of modulating the 5-lipoxygenase (5-LO) pathway that plays key roles in lipid signaling and inflammation. These computational approaches led to the identification of nine natural products that either directly inhibit the activity of the 5-LO enzyme or affect the cellular 5-LO pathway. Further investigation of one of these molecules, deltonin, led us to discover a new cell-type-selective mechanism of action. Our ML approach helped deorphanize natural products as well as shed light on their mechanisms and can be broadly applied to other use cases in chemical biology
Recommended from our members
Machine Learning Uncovers Natural Product Modulators of the 5-Lipoxygenase Pathway and Facilitates the Elucidation of Their Biological Mechanisms.
Publication status: PublishedMachine learning (ML) models have made inroads into chemical sciences, with optimization of chemical reactions and prediction of biologically active molecules being prime examples thereof. These models excel where physical experiments are expensive or time-consuming, for example, due to large scales or the need for materials that are difficult to obtain. Studies of natural products suffer from these issues─this class of small molecules is known for its wealth of structural diversity and wide-ranging biological activities, but their investigation is hindered by poor synthetic accessibility and lack of scalability. To facilitate the evaluation of these molecules, we designed ML models that predict which natural products can interact with a particular target or a relevant pathway. Here, we focused on discovering natural products that are capable of modulating the 5-lipoxygenase (5-LO) pathway that plays key roles in lipid signaling and inflammation. These computational approaches led to the identification of nine natural products that either directly inhibit the activity of the 5-LO enzyme or affect the cellular 5-LO pathway. Further investigation of one of these molecules, deltonin, led us to discover a new cell-type-selective mechanism of action. Our ML approach helped deorphanize natural products as well as shed light on their mechanisms and can be broadly applied to other use cases in chemical biology
Recommended from our members
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases
Recommended from our members
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.
Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases
Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.
Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C-C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody-drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules
Nature has evolved
intricate machinery to target and
degrade RNA,
and some of these molecular mechanisms can be adapted for therapeutic
use. Small interfering RNAs and RNase H-inducing oligonucleotides
have yielded therapeutic agents against diseases that cannot be tackled
using protein-centered approaches. Because these therapeutic agents
are nucleic acid-based, they have several inherent drawbacks which
include poor cellular uptake and stability. Here we report a new approach
to target and degrade RNA using small molecules, proximity-induced
nucleic acid degrader (PINAD). We have utilized this strategy to design
two families of RNA degraders which target two different RNA structures
within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral
pseudoknot. We demonstrate that these novel molecules degrade their
targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy
allows any RNA binding small molecule to be converted into a degrader,
empowering RNA binders that are not potent enough to exert a phenotypic
effect on their own. PINAD raises the possibility of targeting and
destroying any disease-related RNA species, which can greatly expand
the space of druggable targets and diseases
Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules
Nature has evolved
intricate machinery to target and
degrade RNA,
and some of these molecular mechanisms can be adapted for therapeutic
use. Small interfering RNAs and RNase H-inducing oligonucleotides
have yielded therapeutic agents against diseases that cannot be tackled
using protein-centered approaches. Because these therapeutic agents
are nucleic acid-based, they have several inherent drawbacks which
include poor cellular uptake and stability. Here we report a new approach
to target and degrade RNA using small molecules, proximity-induced
nucleic acid degrader (PINAD). We have utilized this strategy to design
two families of RNA degraders which target two different RNA structures
within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral
pseudoknot. We demonstrate that these novel molecules degrade their
targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy
allows any RNA binding small molecule to be converted into a degrader,
empowering RNA binders that are not potent enough to exert a phenotypic
effect on their own. PINAD raises the possibility of targeting and
destroying any disease-related RNA species, which can greatly expand
the space of druggable targets and diseases