Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies

Heald, Alison E.; Iversen, Patrick L.; Saoud, Jay; Sazani, Peter; Charleston, Jay S.; Axtelle, Tim; Wong, Michael; Smith, William B.; Vutikullird, Apinya; Kaye, Edward M.

doi:10.1128/aac.03442-14

Cited by 73 publications

(52 citation statements)

References 8 publications

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“…Several experimental treatments have been administered to a select few individuals. However, the low number of study participants has made the efficacy of these treatments difficult to assess 2–4 . Furthermore, many of these treatments involve siRNA or monoclonal antibody cocktails that are difficult and expensive to procure 5, 6 .…”

Section: Introductionmentioning

confidence: 99%

In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors

Glanzer

Byrne

McCoy

et al. 2016

Bioorganic & Medicinal Chemistry

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Ebola virus continues to be problematic as sporadic outbreaks in Africa continue to arise, and as terrorist organizations have considered the virus for bioterrorism use. Several proteins within the virus have been targeted for antiviral chemotherapy, including VP35, a dsRNA binding protein that promotes viral replication, protects dsRNA from degradation, and prevents detection of the viral genome by immune complexes. To augment the scope of our antiviral research, we have now employed molecular modeling techniques to enrich the population of compounds for further testing in vitro. In the initial docking of a static VP35 structure with an 80,000 compound library, 40 compounds were selected, of which four compounds inhibited VP35 with IC50 < 200uM, with the best compounds having an IC50 of 20 uM. By superimposing 26 VP35 structures, we determined four aspartic acid residues were highly flexible and the docking was repeated under flexible parameters. Of 14 compounds chosen for testing, five compounds inhibited VP35 with IC50 < 200uM and one compound with an IC50 of 4 uM. These studies demonstrate the value of docking in silico for enriching compounds for testing in vitro, and specifically using multiple structures as a guide for detecting flexibility and provide a foundation for further development of small molecule inhibitors directed towards VP35.

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Section: Introductionmentioning

confidence: 99%

In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors

Glanzer

Byrne

McCoy

et al. 2016

Bioorganic & Medicinal Chemistry

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show abstract

“…Several promising therapeutic candidates are currently being investigated, but none are FDA approved. Strategies such as treatment with antisense oligonucleotides, antibody-based therapies, and treatment with small molecules directed against specific viral as well as cellular factors have been tested, but the outcomes have been mixed (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Additionally, many of these therapies target only closely related strains of Ebola virus, making the development of treatments for other species of Ebola virus and Marburg virus a priority.…”

mentioning

confidence: 99%

Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors

Anantpadma

Kouznetsova

Wang

et al. 2016

Antimicrob Agents Chemother

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“…A preliminary pharmacokinetic study of intravenous AVI-7537 was conducted in 30 healthy, adult male and female subjects. 42 Varying doses of AVI-7537 (0.005 mg/kg to 4.5 mg/kg) had a T max of 0.5 hours and a plasma half-life ranging from 2 to 4 hours; approximately 40% of a dose is excreted in the urine. Ongoing studies in nonhuman primates and humans will further evaluate the drug's safety and efficacy as well as dosing.…”

Section: Antiviral Therapymentioning

confidence: 99%