Julie Sotsky - Academia.edu (original) (raw)

Papers by Julie Sotsky

Pathogens and disease, Jan 9, 2015

Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of ... more Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of disease manifestations, including severe bacterial pneumonia. Recently, clinics have reported a rise in nosocomial infections with multidrug resistant (MDR) species, including MDR strains of P. aeruginosa. In order to quickly evaluate the efficacy of new therapeutics for MDR infections, highly reproducible and validated animal models need to be developed for pre-clinical testing. Here we describe the characterization of two murine models to study MDR P. aeruginosa respiratory disease. We evaluated and compared these models using a non-invasive intratracheal instillation method and established the 50% lethal dose, course of infection, biometric parameters of disease, and degree of pneumonia development for each model. Further, we tested meropenem as a proof-of-concept therapeutic and report efficacy data that suggests that the leukopenic model could serve a robust pre-clinical model to te...

ABSTRACT Alphaviruses like Venezuelan Equine Encephalitis Virus (VEEV) are enveloped, positive-se... more ABSTRACT Alphaviruses like Venezuelan Equine Encephalitis Virus (VEEV) are enveloped, positive-sense, single stranded RNA viruses that are geographically widely distributed. They are arthropod-borne viruses that are known to cause rash, arthritis, encephalitis, and death in humans. Of the more than 30 alphavirus pathogens known, about a third contributes to human disease, and currently there are no FDA approved treatments available for any of them. A renewed interest to find effective therapeutic leads for development has emerged due to the lack of effective countermeasures for these pathogens, the increased incidence of their prevalence with global climate changes, and the ease with which they can and have been weaponized as biological threats. VEEV vaccines to date show insufficient efficacy or adverse side effects that limit their use, and disclosed literature compounds possess weak anti-VEEV potency and/or involve host-mediated mechanisms of action, contributing to off-target effects. The high throughput-screen of the MLSMR revealed a subset of scaffolds that inhibited a VEEV-induced cytopathic effect in the low micromolar range. Medicinal chemistry optimization resulted in the development of ML336, a first-in-class probe that inhibited a VEEV-induced cytopathic effect in three strains of the virus (TC-83, V3526, and Trinidad donkey) in the low nanomolar range without showing cytotoxicity (> 50 μM, selectivity index > 1500). Furthermore, ML336 dramatically reduced viral titer (> 7.2 log) below a 1 μM compound concentration and features a favorable in vitro pharmacokinetic profile which includes moderate blood-brain barrier permeability. Importantly, ML336 appears to target the VEEV non-structural protein 2 (nsP2) which is necessary for transcription and replication of viral RNA. This finding alone distinguishes ML336 from all other compounds described to date, and in combination with its overall profile, makes it an ideal candidate for further in vivo development.

PLoS pathogens, 2014

Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equin... more Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was d...

Journal of Medicinal Chemistry, 2014

Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause s... more Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC 50 = 0.8 μM), limited cytotoxic liability (CC 50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC 50 = 0.02−0.04 μM, CC 50 > 50 μM) while limiting in vitro viral replication (EC 90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg −1 day −1 and viral replication appeared to be inhibited through interference of viral nonstructural proteins.

Pathogens and disease, Jan 9, 2015

Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of ... more Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of disease manifestations, including severe bacterial pneumonia. Recently, clinics have reported a rise in nosocomial infections with multidrug resistant (MDR) species, including MDR strains of P. aeruginosa. In order to quickly evaluate the efficacy of new therapeutics for MDR infections, highly reproducible and validated animal models need to be developed for pre-clinical testing. Here we describe the characterization of two murine models to study MDR P. aeruginosa respiratory disease. We evaluated and compared these models using a non-invasive intratracheal instillation method and established the 50% lethal dose, course of infection, biometric parameters of disease, and degree of pneumonia development for each model. Further, we tested meropenem as a proof-of-concept therapeutic and report efficacy data that suggests that the leukopenic model could serve a robust pre-clinical model to te...

ABSTRACT Alphaviruses like Venezuelan Equine Encephalitis Virus (VEEV) are enveloped, positive-se... more ABSTRACT Alphaviruses like Venezuelan Equine Encephalitis Virus (VEEV) are enveloped, positive-sense, single stranded RNA viruses that are geographically widely distributed. They are arthropod-borne viruses that are known to cause rash, arthritis, encephalitis, and death in humans. Of the more than 30 alphavirus pathogens known, about a third contributes to human disease, and currently there are no FDA approved treatments available for any of them. A renewed interest to find effective therapeutic leads for development has emerged due to the lack of effective countermeasures for these pathogens, the increased incidence of their prevalence with global climate changes, and the ease with which they can and have been weaponized as biological threats. VEEV vaccines to date show insufficient efficacy or adverse side effects that limit their use, and disclosed literature compounds possess weak anti-VEEV potency and/or involve host-mediated mechanisms of action, contributing to off-target effects. The high throughput-screen of the MLSMR revealed a subset of scaffolds that inhibited a VEEV-induced cytopathic effect in the low micromolar range. Medicinal chemistry optimization resulted in the development of ML336, a first-in-class probe that inhibited a VEEV-induced cytopathic effect in three strains of the virus (TC-83, V3526, and Trinidad donkey) in the low nanomolar range without showing cytotoxicity (> 50 μM, selectivity index > 1500). Furthermore, ML336 dramatically reduced viral titer (> 7.2 log) below a 1 μM compound concentration and features a favorable in vitro pharmacokinetic profile which includes moderate blood-brain barrier permeability. Importantly, ML336 appears to target the VEEV non-structural protein 2 (nsP2) which is necessary for transcription and replication of viral RNA. This finding alone distinguishes ML336 from all other compounds described to date, and in combination with its overall profile, makes it an ideal candidate for further in vivo development.

PLoS pathogens, 2014

Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equin... more Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was d...

Journal of Medicinal Chemistry, 2014

Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause s... more Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC 50 = 0.8 μM), limited cytotoxic liability (CC 50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC 50 = 0.02−0.04 μM, CC 50 > 50 μM) while limiting in vitro viral replication (EC 90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg −1 day −1 and viral replication appeared to be inhibited through interference of viral nonstructural proteins.