A5090698053- SARS-CoV-2 and COVID-19 Research
- Respiratory viral infections research
- COVID-19 Clinical Research Studies
- Viral gastroenteritis research and epidemiology
- Viral Infections and Immunology Research
- Viral Infections and Vectors
- Mosquito-borne diseases and control
- SARS-CoV-2 detection and testing
- Animal Virus Infections Studies
- Virus-based gene therapy research
- Plant Virus Research Studies
- interferon and immune responses
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- Bacteriophages and microbial interactions
- Viral Infections and Outbreaks Research
- Calcium signaling and nucleotide metabolism
- Malaria Research and Control
- Immunodeficiency and Autoimmune Disorders
- Invertebrate Immune Response Mechanisms
- Research on Leishmaniasis Studies
- Insect symbiosis and bacterial influences
- Silk-based biomaterials and applications
- Polyomavirus and related diseases
- Cytomegalovirus and herpesvirus research
Ark Therapeutic (United States)
2024
Gilead Sciences (United States)
2020-2024
Harvard University
2016-2019
Boston VA Research Institute
2019
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of novel viral disease COVID-19. With no approved therapies, this pandemic illustrates urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits replication in human lung cells primary airway epithelial cultures (EC50 = 0.01 μM). Weaker activity observed Vero E6 1.65 μM) because their low capacity to metabolize RDV....
Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence and rapid spread multiple variants throughout pandemic, which Omicron is currently predominant variant circulating worldwide. SARS-CoV-2 concern/variants interest (VOC/VOI) have evidence increased viral transmission, disease severity, or decreased effectiveness vaccines neutralizing antibodies. Remdesivir (RDV [VEKLURY]) a nucleoside analog prodrug first FDA-approved antiviral...
A discovery program targeting respiratory syncytial virus (RSV) identified
Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming bioactive triphosphate 2-NTP. 2-NTP, analog ATP, inhibits SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription viral RNA. Strong clinical results for have prompted interest in oral approaches to generate Here, we describe discovery a 5′-isobutyryl ester 2 (GS-5245, Obeldesivir, 3) has low cellular cytotoxicity 3–7-fold improved delivery...
Abstract Anelloviruses are nonpathogenic viruses that comprise a major portion of the human virome. Despite being ubiquitous in population, anelloviruses (ANVs) remain poorly understood. Basic features virus, such as identity its capsid protein and structure viral particle, have been unclear until now. Here, we use cryogenic electron microscopy to describe first an ANV-like particle. The formed by 60 jelly roll domain-containing ANV proteins, forms icosahedral particle core from which spike...
Remdesivir (RDV; GS-5734, Veklury), the first FDA-approved antiviral to treat COVID-19, is a single-diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV taken up in target cells and metabolized multiple steps form active nucleoside triphosphate (TP) (GS-443902), which, turn, acts as potent selective inhibitor viral RNA polymerases.
Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as first treatment for hospitalized COVID-19 patients. Furthermore, has been or authorized emergency use more than 50 countries. To make convenient non-hospitalized earlier disease, alternative routes of administration are being evaluated. Here, we investigated pharmacokinetics and efficacy administered...
Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there no effective oral therapeutics for RSV infection. Obeldesivir (ODV) an orally bioavailable prodrug the nucleoside analog GS-441524, which converted intracellularly to its active triphosphate inhibits RNA polymerase. Here we report potent antiviral activity ODV against geographically temporally diverse A B clinical isolates (EC 50 :...
SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of novel pandemic viral disease COVID-19. With no approved therapies, this illustrates urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug an adenosine analog, potently inhibits replication human lung cells primary airway epithelial cultures (EC 50 = 0.01 μM). Weaker...
Vaccines and antivirals to combat dengue, Zika, other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses propensity non-neutralizing, cross-reactive antibodies facilitate cellular infection increase disease severity. As an alternative, direct-acting targeting envelope protein, E, have potential act via analogous mode action without risk antibody-dependent enhancement disease. We previously...
Abstract The significant impact of the human virome on physiology is beginning to emerge thanks modern sequencing methods and bioinformatic tools 1 . Anelloviruses, principal constituent commensal virome, are universally acquired in infancy found throughout body 2,3,4 Since discovery original torque teno virus 1997 5 , three genera Anelloviridae family, each extremely diverse genetically, have been humans. These viruses elicit weak immune responses that permit multiple strains co-exist...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of novel pandemic viral disease COVID-19. With no approved therapies, this illustrates urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug an adenosine analog, potently inhibits replication human lung cells primary airway epithelial cultures (EC50 = 0.01 µM). Weaker activity...
Abstract Remdesivir 1 is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 ( 2 ) into lung cells thereby forming bioactive triphosphate 2-NTP . , analog ATP, inhibits SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription viral RNA. Strong clinical results for have prompted interest in oral approaches to generate Here we describe discovery a 5’-isobutyryl ester GS-5245, Obeldesivir, 3 has low cellular cytotoxicity three seven-fold improved delivery...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 pandemic, has infected over 260 million people past years. Remdesivir (RDV, VEKLURY®) is currently only antiviral therapy fully approved by FDA for treatment COVID-19. The parent nucleoside RDV, GS-441524, exhibits activity against numerous viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV most assays. Here we find both human alveolar and bronchial primary cells,...
Abstract Background Remdesivir (RDV, Veklury) is the first FDA-approved direct-acting antiviral treatment for COVID-19. While RDV requires IV administration, obeldesivir (ODV, GS-5245) an oral prodrug of GS-441524, parent nucleoside RDV, designed effective delivery. ODV being tested in two Phase 3 clinical studies outpatient Methods In vitro activity against SARS-CoV-2 was assessed A549-hACE2 cells. vivo therapeutic efficacy evaluated mouse, ferret, and African Green Monkey (AGM) models....
Abstract Acute respiratory viral infections (ARVI), such as pneumovirus and picornavirus infections, exacerbate disease in COPD asthma patients. A research program targeting syncytial virus (RSV) led to the discovery of GS-7682 ( 1 ) a novel phosphoramidate prodrug 4′-CN-4-aza-7,9-dideazaadenosine C -nucleoside GS-646089 2 with broad antiviral activity against RSV EC 50 = 3-46 nM, human metapneumovirus (hMPV) 210 ± rhinovirus (RV) 54-61 enterovirus (EV) 83-90 nM. Prodrug optimization for...
ABSTRACT The development of safe and effective broad-spectrum antivirals that target the replication machinery respiratory viruses is high priority in pandemic preparedness programs. Here, we studied mechanism action a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) prototypic viruses. GS-646939 active 5′-triphosphate (TP) metabolite 4ʹ-cyano modified C -adenosine phosphoramidate prodrug GS-7682. Enzyme kinetics show RdRps human rhinovirus type 16...
Abstract Genetic variation of SARS-CoV-2 has resulted in the emergence and rapid spread multiple variants throughout pandemic, which Omicron is currently predominant variant circulating worldwide. concern or interest (VOC/VOI) have evidence increased viral transmission, disease severity, decreased effectiveness vaccines neutralizing antibodies. Remdesivir (RDV, VEKLURY ® ) a nucleoside analog prodrug first FDA-approved antiviral treatment COVID-19. Here we present comprehensive activity...