A5018500822- SARS-CoV-2 and COVID-19 Research
- Influenza Virus Research Studies
- Respiratory viral infections research
- COVID-19 Clinical Research Studies
- Viral Infections and Immunology Research
- Computational Drug Discovery Methods
- interferon and immune responses
- Virus-based gene therapy research
- Viral Infections and Outbreaks Research
- RNA and protein synthesis mechanisms
- Calpain Protease Function and Regulation
- Viral gastroenteritis research and epidemiology
- Herpesvirus Infections and Treatments
- Mosquito-borne diseases and control
- Poxvirus research and outbreaks
- Whipple's Disease and Interleukins
- Peptidase Inhibition and Analysis
- vaccines and immunoinformatics approaches
- Inhalation and Respiratory Drug Delivery
- Venomous Animal Envenomation and Studies
- Viral Infections and Vectors
- Long-Term Effects of COVID-19
- Cytomegalovirus and herpesvirus research
- Immune Response and Inflammation
- Biochemical and Molecular Research
Utah State University
2016-2025
University of Arizona
2020
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part the healthcare response to countering ongoing threat presented COVID-19. Here, we report discovery and characterization PF-07321332, orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human activity excellent off-target selectivity vivo safety profiles. PF-07321332...
A new coronavirus SARS-CoV-2, also called novel 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus COVID-19, which highly contagious has an overall mortality rate of 6.35% May 26, 2020. There no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery inhibitors targeting the main protease (M
The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have γ-lactam glutamine surrogate at the P1 position, we recently found that several hydrophobic moieties site, including calpain II and XII, which are also active against human cathepsin L, host important for viral entry. In this study, solved x-ray crystal structures in complex with XII three analogs GC-376 structure inhibitor confirmed S1 pocket can accommodate methionine side chain,...
Host-cell cysteine proteases play an essential role in the processing of viral spike protein SARS coronaviruses. K777, irreversible, covalent inactivator that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 infectivity several host cells: Vero E6 (EC50< 74 nM), HeLa/ACE2 (4 Caco-2 (EC90 = 4.3 μM), and A549/ACE2 (<80 nM). Infectivity Calu-3 cells depended on cell line assayed. If Calu-3/2B4 was used, EC50 7 nM, but ATCC without ACE2 enrichment, >10 μM. There no toxicity to...
Abstract The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation replication cycle. Based on conservation of substrate binding pockets across coronaviruses using screening, we identified four structurally distinct lead compounds that inhibit protease. After evaluation their specificity, cellular antiviral potency, metabolic stability, water solubility, prioritized GC376 scaffold as being...
Abstract Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein proteins. As a result, promising target inhibition small-molecule therapeutics. Here we design series...
Despite the record-breaking discovery, development and approval of vaccines antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained fourth leading cause death in world third highest United States 2022. Here, we report discovery characterization PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, component ritonavir-boosted therapy Paxlovid. We demonstrate
As the COVID-19 pandemic continues to unfold, morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four main protease (Mpro) inhibitors including boceprevir, calpain II XII, GC-376 with potent antiviral activity against infectious in cell culture. In this study, we further characterized mechanism of action these compounds using pseudovirus neutralization assay. It was found that XII have a dual by inhibiting both viral...
Abstract To identify potential therapeutic stop-gaps for SARS-CoV-2, we evaluated a library of 1,670 approved and reference compounds in an unbiased, cellular image-based screen their ability to suppress the broad impacts SARS-CoV-2 virus on phenomic profiles human renal cortical epithelial cells using deep learning. In our assay, remdesivir is only antiviral tested with strong efficacy, neither chloroquine nor hydroxychloroquine have any beneficial effect this cell model, small number not...
Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and 116 cases March, 2021. Small-molecule inhibitors reverse disease severity have proven difficult to discover. One of the key approaches been widely applied an effort speed up translation drugs drug repurposing. A few shown
The COVID-19 pandemic highlights the need for platform technologies enabling rapid development of vaccines emerging viral diseases. current target SARS-CoV-2 spike (S) protein and thus far have shown tremendous efficacy. However, cold-chain distribution, a prime-boost administration schedule, emergence variants concern (VOCs) call diligence in novel vaccine approaches. We studied 13 peptide epitopes from identified three neutralizing that are highly conserved among VOCs. Monovalent trivalent...
ABSTRACT Favipiravir (T-705 [6-fluoro-3-hydroxy-2-pyrazinecarboxamide]) and oseltamivir were combined to treat influenza virus A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), A/Duck/MN/1525/81 (H5N1) infections. T-705 alone inhibited viruses in cell culture at 1.4 4.3 μM. Oseltamivir these three cells 3.7, 0.02, 0.16 μM neuraminidase assays 0.94, 0.46, 2.31 nM, respectively. Oral treatments given twice daily mice for 5 7 days starting, generally, 24 h after infection. Survival resulting from of...
To determine the metabolism of favipiravir (T-705, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) to its ribosylated, triphosphorylated form (T-705 RTP) in uninfected and influenza A/Duck/MN/1525/81 (H5N1) virus-infected cells. Effects treatment on intracellular guanosine triphosphate (GTP) pools virus-inhibitory activity were also assessed. A strong anion exchange HPLC separation method with UV detection was used quantify T-705 RTP GTP levels Madin–Darby canine kidney Antiviral determined by...
ABSTRACT An amantadine-resistant influenza A/Duck/MN/1525/81 (H5N1) virus was developed from the low-pathogenic North American wild-type (amantadine-sensitive) for studying treatment of infections in cell culture and mice. Double combinations amantadine, oseltamivir (or culture-active form, carboxylate), ribavirin were used. Amantadine-oseltamivir carboxylate amantadine-ribavirin showed synergistic interactions over a range doses against Madin-Darby canine kidney (MDCK) culture, but...
A novel coronavirus SARS-CoV-2, also called 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus COVID-19, which highly contagious has an overall mortality rate of 6.96% May 4, 2020. There no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery inhibitors targeting the main protease (M pro ). Using FRET-based enzymatic assay, several including boceprevir,...
With the rapidly evolving SARS-CoV-2 variants of concern, there is an urgent need for discovery further treatments coronavirus disease (COVID-19). Drug repurposing one most rapid strategies addressing this need, and numerous compounds have already been selected in vitro testing by several groups. These led to a growing database molecules with activity against virus. Machine learning models can assist drug through prediction best based on previously published data. Herein, we implemented...
SARS-CoV-2 has caused a global pandemic, and taken over 1.7 million lives as of mid-December, 2020. Although great progress been made in the development effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines market, there is still an unmet need essential antiviral drugs therapeutic impact for treatment moderate-to-severe COVID-19. Towards this goal, high-throughput assay was used screen nsp15 uracil-dependent endonuclease (endoU) function...
Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy potential viral resistance. The SARS-CoV-2 papain-like protease (PL
Abstract Immunization programs against SARS-CoV-2 with commercial intramuscular vaccines prevent disease but are less efficient in preventing infections. Mucosal can provide improved protection transmission, ideally for different variants of concern (VOCs) and related sarbecoviruses. Here, we report a multi-antigen, intranasal vaccine, NanoSTING-SN (NanoSTING-Spike-Nucleocapsid), eliminates virus replication both the lungs nostrils upon challenge pathogenic Delta VOC. We further demonstrate...
The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, repurposing and cotreatments, in particular focusing on existing candidates host-directed antivirals (HDAs). developmental IMU-838, currently being investigated a phase 2b trial patients suffering from autoimmune diseases, represents an inhibitor human dihydroorotate dehydrogenase (DHODH) with recently proven antiviral activity vitro...