ChemInform Abstract: ALKYLATED PYRIMIDINE DERIVATIVES AS ANTIVIRAL AGENTS PART 3, SYNTHESIS AND ANTIVIRAL EFFECT OF 5-ETHYLURACIL NUCLEOSIDES

1973 ◽  
Vol 4 (42) ◽  
pp. no-no
Author(s):  
M. MURAOKA ◽  
T. UEDA
Keyword(s):  
Antiviral Agents ◽  
Antiviral Effect ◽  
Pyrimidine Derivatives

scholarly journals Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

2021 ◽  
Author(s):  
Chamandi S. Dampalla ◽  
Jian Zhang ◽  
Krishani Dinali Perera ◽  
Lok-Yin Roy Wong ◽  
David K. Meyerholz ◽  
...  
Keyword(s):  
Post Infection ◽  
Structural Investigation ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Global Public Health ◽  
Infection Treatment ◽  
Lethal Infection ◽  
Deuterated Derivative ◽  
Human Coronaviruses ◽  
Potent Inhibitory Activity

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and was proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 hr post infection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

scholarly journals In vitro Assessment of Antiviral Effect of Natural Compounds on Porcine Epidemic Diarrhea Coronavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Manuel Gómez-García ◽  
Héctor Puente ◽  
Héctor Argüello ◽  
Óscar Mencía-Ares ◽  
Pedro Rubio ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Formic Acid ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Optical Microscope ◽  
Dependent Manner ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

Organic acid and essential oils (EOs), well-known antimicrobials, could also possess antiviral activity, a characteristic which has not been completely addressed up to now. In this study, the effect of two organic acids (formic acid and sodium salt of coconut fatty acid distillates) and two single EO compounds (thymol and cinnamaldehye) was evaluated against porcine epidemic diarrhea virus (PEDV). The concentration used for each compound was established by cytotoxicity assays in Vero cells. The antiviral activity was then evaluated at three multiplicities of infection (MOIs) through visual cytopathic effect (CPE) evaluation and an alamarBlue assay as well as real-time reverse-transcription PCR (RT-qPCR) and viral titration of cell supernatants. Formic acid at at a dose of 1,200 ppm was the only compound which showed antiviral activity, with a weak reduction of CPE caused by PEDV. Through the alamarBlue fluorescence assay, we showed a significant anti-CPE effect of formic acid which could not be observed by using an inverted optical microscope. RT-qPCR and infectivity analysis also showed that formic acid significantly reduced viral RNA and viral titers in a PEDV MOI-dependent manner. Our results suggest that the antiviral activity of formic acid could be associated to its inhibitory effect on viral replication. Further studies are required to explore the anti-PEDV activity of formic acid under field conditions alone or together with other antiviral agents.

scholarly journals Developing a Biomimetic Evaluation Method for Antiviral Coatings Using Artificial Saliva Droplets.

2021 ◽  
Author(s):  
Naoki Tanaka ◽  
Nobuhiro Miyamae
Keyword(s):  
Evaluation Method ◽  
Respiratory Infections ◽  
Artificial Saliva ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Indirect Contact ◽  
Coating Agent ◽  
Active Virus ◽  
Antiviral Effects ◽  
Mucous Membranes

Respiratory infections pose a serious threat worldwide, and many new antiviral agents and coatings have been developed to reduce the overall risk of viral infection. Here, we evaluate the methodology used to test these antiviral coatings and developed a novel system that is more similar to real-world conditions. Contact infection is largely mediated via contact with saliva containing the active virus released as droplets by coughing or sneezing, with these droplets adhering to objects and surfaces and subsequently entering the human body via indirect contact with the mucous membranes. Here, we evaluated the antiviral effect of a known antiviral coating agent using an artificial saliva based system, where artificial saliva containing phages were sprayed onto the antiviral coating under various conditions associated with viral replication and infectious spread. We used a commercially available antiviral coating in this evaluation, and M13 bacteriophages as model viruses. This method enables simple biomimetic evaluations of any product antiviral effects.

scholarly journals Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra-O-Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Teresa Merino-Ramos ◽  
Nereida Jiménez de Oya ◽  
Juan-Carlos Saiz ◽  
Miguel A. Martín-Acebes
Keyword(s):  
Lipid Metabolism ◽  
West Nile Virus ◽  
Zika Virus ◽  
Regulatory Element ◽  
Antiviral Agents ◽  
Nordihydroguaiaretic Acid ◽  
Antiviral Effect ◽  
West Nile ◽  
Sterol Regulatory Element ◽  
Positive Strand Rna

ABSTRACT Flaviviruses are positive-strand RNA viruses distributed all over the world that infect millions of people every year and for which no specific antiviral agents have been approved. These viruses include the mosquito-borne West Nile virus (WNV), which is responsible for outbreaks of meningitis and encephalitis. Considering that nordihydroguaiaretic acid (NDGA) has been previously shown to inhibit the multiplication of the related dengue virus and hepatitis C virus, we have evaluated the effect of NDGA, and its methylated derivative tetra-O-methyl nordihydroguaiaretic acid (M4N), on the infection of WNV. Both compounds inhibited the infection of WNV, likely by impairing viral replication. Since flavivirus multiplication is highly dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the sterol regulatory element-binding proteins (SREBP) pathway. Remarkably, we observed that other structurally unrelated inhibitors of the SREBP pathway, such as PF-429242 and fatostatin, also reduced WNV multiplication, supporting that the SREBP pathway may constitute a druggable target suitable for antiviral intervention against flavivirus infection. Moreover, treatment with NDGA, M4N, PF-429242, and fatostatin also inhibited the multiplication of the mosquito-borne flavivirus Zika virus (ZIKV), which has been recently associated with birth defects (microcephaly) and neurological disorders. Our results point to SREBP inhibitors, such as NDGA and M4N, as potential candidates for further antiviral development against medically relevant flaviviruses.

scholarly journals KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo

2013 ◽  
Vol 58 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Sophie Duraffour ◽  
Robert Drillien ◽  
Kazuhiro Haraguchi ◽  
Jan Balzarini ◽  
Dimitri Topalis ◽  
...  
Keyword(s):  
Binding Site ◽  
Nucleoside Analogue ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Cross Resistance ◽  
Cowpox Virus ◽  
Herpes Simplex Virus 1 ◽  
Lethal Challenge ◽  
Atp Binding Site

ABSTRACTThe availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1′-methyl-substituted 4′-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses.In vitro, KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK;J2R) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2′-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1′-carbon-substituted 4′-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.

scholarly journals Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

2021 ◽  
Vol 118 (29) ◽  
pp. e2101555118
Author(s):  
Chamandi S. Dampalla ◽  
Jian Zheng ◽  
Krishani Dinali Perera ◽  
Lok-Yin Roy Wong ◽  
David K. Meyerholz ◽  
...  
Keyword(s):  
Structural Investigation ◽  
Antiviral Agents ◽  
Antiviral Effect ◽  
Global Public Health ◽  
Histopathological Changes ◽  
Lethal Infection ◽  
Public Health Threat ◽  
Deuterated Derivative ◽  
Human Coronaviruses ◽  
Potent Inhibitory Activity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2–treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

scholarly journals Identification of the phytobioactive Polygonum cuspidatum as an antiviral source for restricting dengue virus entry

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu-Ting Kuo ◽  
Ching-Hsuan Liu ◽  
Jin-Wei Li ◽  
Chien-Ju Lin ◽  
Alagie Jassey ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Antiviral Agents ◽  
Cell Types ◽  
Antiviral Effect ◽  
Denv Infection ◽  
Polygonum Cuspidatum ◽  
Tropical Regions ◽  
Viral Attachment ◽  
Excellent Starting Point ◽  
Starting Point

Abstract Dengue virus (DENV) is a mosquito-borne pathogen that is becoming a serious global threat, owing to its rising incidence in inter-tropical regions that yield over 50 million annual infections. There are currently no approved antiviral agents for the management of dengue, and recent shortcomings in its immunization called for immediate action to develop effective drugs with prophylactic ability to better manage its infection. In an attempt to discover novel antiviral sources, we identified the medicinal herb Polygonum cuspidatum (PC) as a bioactive botanical material against DENV infectivity. Specifically, the methanolic extract from PC rhizomes (PCME) potently inhibited DENV infection without causing significant cytotoxicity. Further examination on the viral life cycle demonstrated that PCME particularly targeted the initial stages of DENV infection, while pre- and post-infection treatments had no effect. More importantly, the PCME could efficiently inactivate DENV free virus particles and block the viral attachment and entry/fusion events without apparently influencing viral replication, egress, and cell-to-cell spread. The antiviral effect of PCME was also recapitulated in infection analysis using DENV pseudoparticles displaying viral structural proteins that mediate DENV particle entry. Besides, PCME treatment also inhibited direct DENV entry into several cell types relevant to its infection and reduced viral infectivity of other members of the Flaviviridae family, including the hepatitis C virus (HCV) and Zika virus (ZIKV). Due to its potency against DENV entry, we suggest that the phytobioactive extract from PC is an excellent starting point as an antiviral source material for further development of therapeutic strategies in the prophylactic management of DENV infection.

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