Rafael M. Couñago
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View article: Identification of spirodioxolane nsP2 helicase inhibitors with antialphaviral activity
Identification of spirodioxolane nsP2 helicase inhibitors with antialphaviral activity Open
Spirodioxolanes were identified as a new series of direct-acting nsP2 helicase inhibitors with activity against alphaviruses. Analogs such as 6b maintained activity against viral mutants with resistance to first-generation nsP2 helicase in…
View article: Enabling Open Machine Learning of Deoxyribonucleic Acid-Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders
Enabling Open Machine Learning of Deoxyribonucleic Acid-Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders Open
Machine learning (ML) is increasingly used in DNA-encoded library (DEL) screening for ligand discovery, but its success depends on access to suitable data sets, which are often proprietary and costly. To overcome this, we present the first…
View article: <i> <b>N</b> </i> -Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad-Spectrum Antialphaviral Activity
<i> <b>N</b> </i> -Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad-Spectrum Antialphaviral Activity Open
The emergence of mosquito-borne alphaviruses that cause chronic arthritis or encephalitis underscores the urgent need for broad-spectrum antiviral therapeutics. The viral nsP2 cysteine protease, which is essential for alphavirus replicatio…
View article: Enabling Open Machine Learning of Deoxyribonucleic Acid-Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders
Enabling Open Machine Learning of Deoxyribonucleic Acid-Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders Open
Machine learning (ML) is increasingly used in DNA-encoded library (DEL) screening for ligand discovery, but its success depends on access to suitable data sets, which are often proprietary and costly. To overcome this, we present the first…
View article: Identification of Spirodioxolane nsP2 Helicase Inhibitors with Antialphaviral Activity
Identification of Spirodioxolane nsP2 Helicase Inhibitors with Antialphaviral Activity Open
We describe the design, synthesis, and antialphaviral activity of spirodioxolane inhibitors targeting the alphavirus nsP2 helicase (nsP2hel). The spirodioxolanes are a new series of direct-acting antivirals that retain key molecular featur…
View article: Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity
Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity Open
Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine 1, a first-in-class inhibitor of the…
View article: Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity
Identification of Direct-Acting nsP2 Helicase Inhibitors with Antialphaviral Activity Open
Alphaviruses are mosquito-borne RNA viruses that pose a significant public health threat, with no FDA-approved antiviral therapeutics available. The nonstructural protein 2 helicase (nsP2hel) is an enzyme involved in unwinding dsRNA essent…
View article: <i>N</i>-Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad Spectrum Antialphaviral Activity
<i>N</i>-Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad Spectrum Antialphaviral Activity Open
The emergence of mosquito-borne alphaviruses that cause chronic arthritis or encephalitis underscores the urgent need for broad-spectrum antiviral therapeutics. The viral nsP2 cysteine protease, which is essential for alphavirus replicatio…
View article: A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity
A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity Open
View article: Discovery and characterization of cell-permeable inhibitors of<i>Leishmania mexicana</i>CLK1 using an in-cell target engagement assay
Discovery and characterization of cell-permeable inhibitors of<i>Leishmania mexicana</i>CLK1 using an in-cell target engagement assay Open
Leishmaniasis is a neglected tropical disease with limited treatment options and significant unmet medical need. Here, we report the development of a bioluminescence resonance energy transfer (BRET)-based target engagement assay in live in…
View article: Identification of a Broadly Acting Inhibitor of the Alphavirus Non-Structural Protein 2 Helicase
Identification of a Broadly Acting Inhibitor of the Alphavirus Non-Structural Protein 2 Helicase Open
Alphaviruses are mosquito-borne viruses that have caused significant outbreaks in the 21 st century. Despite multiple recent outbreaks, there are no approved antiviral drugs to treat any alphavirus infection. Therefore, developing broadly …
View article: Fragment Screening by Weak Affinity Chromatography Identifies Ligands for <i>Neisseria gonorrhoeae</i> Undecaprenyl Diphosphate Synthase
Fragment Screening by Weak Affinity Chromatography Identifies Ligands for <i>Neisseria gonorrhoeae</i> Undecaprenyl Diphosphate Synthase Open
The rapid rise of antimicrobial resistance in Neisseria gonorrhoeae underscores the urgent need for new therapeutic strategies. Undecaprenyl diphosphate synthase (UPPS), an essential enzyme in bacterial cell wall biosynthesis, has emerged …
View article: An Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity
An Enantioselective Chemical Probe for Chikungunya nsP2 Helicase with Antialphaviral Activity Open
Chikungunya virus (CHIKV) replication relies on the multifunctional nsP2 protein, making it an attractive target for antiviral drug discovery. Here, we report the resolution of oxaspiropiperidine 1 , a first-in-class inhibitor of the CHIKV…
View article: Chemoproteomic Profiling of <i>C. albicans</i> for Characterization of Antifungal Kinase Inhibitors
Chemoproteomic Profiling of <i>C. albicans</i> for Characterization of Antifungal Kinase Inhibitors Open
Candida albicans is a major cause of systemic candidiasis, a severe fungal infection with a ∼40% mortality rate. Yck2, a casein kinase 1 (CK1) in C. albicans, is targeted by antifungal inhibitors YK-I-02 (YK) and MN-I-157 (MN…
View article: Identification of Direct-acting nsP2 Helicase Inhibitors with Antialphaviral Activity
Identification of Direct-acting nsP2 Helicase Inhibitors with Antialphaviral Activity Open
Alphaviruses are mosquito-borne RNA viruses that pose a significant public health threat, with no FDA-approved antiviral therapeutics available. The non-structural protein 2 helicase (nsP2hel) is an enzyme involved in unwinding dsRNA essen…
View article: A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity
A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity Open
View article: Editorial: Exploring novel approaches to small molecule kinase inhibitors in cancer treatment
Editorial: Exploring novel approaches to small molecule kinase inhibitors in cancer treatment Open
View article: Development of a Second-Generation, <i>In Vivo</i> Chemical Probe for PIKfyve
Development of a Second-Generation, <i>In Vivo</i> Chemical Probe for PIKfyve Open
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell…
View article: Chemoproteomic Profiling of <i>C. albicans</i> for Characterization of Anti-fungal Kinase Inhibitors
Chemoproteomic Profiling of <i>C. albicans</i> for Characterization of Anti-fungal Kinase Inhibitors Open
Candida albicans is a growing health concern as the leading causal agent of systemic candidiasis, a life-threatening fungal infection with a mortality rate of ∼40% despite best available therapy. Yck2, a fungal casein kinase 1 (CK1) family…
View article: Front Cover: (<i>S</i>)‐ML‐SA1 Activates Autophagy via TRPML1‐TFEB Pathway (ChemBioChem 22/2024)
Front Cover: (<i>S</i>)‐ML‐SA1 Activates Autophagy via TRPML1‐TFEB Pathway (ChemBioChem 22/2024) Open
View article: A Covalent Chemical Probe for Chikungunya nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity
A Covalent Chemical Probe for Chikungunya nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity Open
View article: Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against <i>Mycobacterium abscessus</i> and <i>Mycobacterium avium</i>, Two Emerging Human Pathogens
Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against <i>Mycobacterium abscessus</i> and <i>Mycobacterium avium</i>, Two Emerging Human Pathogens Open
Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key…
View article: Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve
Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve Open
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinom…
View article: Enabling Open Machine Learning of DNA Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders
Enabling Open Machine Learning of DNA Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders Open
Recent advances in DNA-encoded library (DEL) screening have created bioactivity datasets containing billions of molecules, unlocking new opportunities for machine learning (ML) in drug discovery. However, most ultra-large DEL libraries are…
View article: Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach
Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach Open
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV nonstruct…
View article: Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2
Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2 Open
The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokine…
View article: Rational exploration of 2,4-diaminopyrimidines as DHFR inhibitors active against Mycobacterium abscessus and Mycobacterium avium, two emerging human pathogens
Rational exploration of 2,4-diaminopyrimidines as DHFR inhibitors active against Mycobacterium abscessus and Mycobacterium avium, two emerging human pathogens Open
Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key…
View article: More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-<i>a</i>]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication
More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-<i>a</i>]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication Open
The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitu…
View article: Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε
Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε Open
Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their…
View article: Combined effect of SAR-endolysin LysKpV475 with polymyxin B and Salmonella bacteriophage phSE-5
Combined effect of SAR-endolysin LysKpV475 with polymyxin B and Salmonella bacteriophage phSE-5 Open
Endolysins are bacteriophage (or phage)-encoded enzymes that catalyse the peptidoglycan breakdown in the bacterial cell wall. The exogenous action of recombinant phage endolysins against Gram-positive organisms has been extensively studied…