Biology subjects

Vermillion, M. S.

Publications and source records attributed to Vermillion, M. S..

4 recordsLinked to original sources

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2024

Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4'-CN-4-Aza-7,9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1) a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV EC50 = 3-46 nM, human metapneumovirus (hMPV) EC50 = 210 {+/-} 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2,3-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses.

biochemistry↗

bioRxiv2022

Characterization of enterovirus D68 infection in four nonhuman primate species

Human enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen that is associated with the development of acute flaccid myelitis (AFM) in children. Currently, there are no approved vaccines or treatments for EV-D68 infection, and there is a paucity of data related to the virus and host specific factors that predict disease severity and progression to the neurologic syndrome. Published animal models of EV-D68 infection to date have been limited to mice, cotton rat and ferrets, and investigation of the susceptibility of nonhuman primate (NHP) species to contemporary EV-D68 isolates has not yet been reported. In this study, we challenged juvenile NHPs - cynomolgus macaques, rhesus macaques, pigtailed macaques, and African green monkeys - with one of five different 2014 or 2018 EV-D68 isolates by the respiratory route. Animals were monitored for clinical respiratory and neurologic signs, and serially collected nasal swabs, bronchoalveolar lavage fluid (BALF) and cerebrospinal fluid (CSF) were evaluated for EV-D68 RNA and infectious virus. Infection with 2014 and 2018 EV-D68 isolates resulted in mild respiratory and gastrointestinal disease in some animals, but no evidence of neurological disease. Neither EV-D68 RNA nor infectious virus could be detected from any sample collected from animals challenged with 2014 EV-D68 isolates. Limited viral shedding - based on viral RNA quantified from nasal swabs and BALF - was detected from some animals infected with 2018 EV-D68 isolates. No virus was detectable in CSF. The rate of seroconversion was 100% for cynomolgus macaques infected with the 2018 EV-D68 isolates, but averaged between 0-50% for the 2014 isolates. Based on the results of this study, there is some evidence that infection with 2018 EV-D68 isolates may be more reliable at establishing limited infection than 2014 EV-D68 isolates. Regardless of virus isolate, however, EV-D68 infection of juvenile NHP species resulted in mild and nonspecific clinical disease and limited viral shedding. These data suggest that further refinements to the NHP model system (e.g., immunosuppression and/or direct viral inoculation) may be required to reproduce EV-D68 infection of the central nervous system and the associated AFM phenotype.

microbiology↗

bioRxiv2020

Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

Mouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human [a]-, {beta}- and {gamma}-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.

physiology↗