scholarly journals Small-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kevin Wittwer ◽  
Danielle E. Anderson ◽  
Kristin Pfeffermann ◽  
Robert M. Cox ◽  
Josef D. Wolf ◽  
...  
Keyword(s):  
Small Molecule ◽  
Measles Virus ◽  
Clinical Signs ◽  
Saimiri Sciureus ◽  
Effective Vaccine ◽  
Virus Eradication ◽  
Virus Shedding ◽  
Polymerase Inhibitor ◽  
Orally Bioavailable ◽  
Measles Outbreaks

AbstractMeasles virus (MeV) is a highly contagious pathogen that enters the human host via the respiratory route. Besides acute pathologies including fever, cough and the characteristic measles rash, the infection of lymphocytes leads to substantial immunosuppression that can exacerbate the outcome of infections with additional pathogens. Despite the availability of effective vaccine prophylaxis, measles outbreaks continue to occur worldwide. We demonstrate that prophylactic and post-exposure therapeutic treatment with an orally bioavailable small-molecule polymerase inhibitor, ERDRP-0519, prevents measles disease in squirrel monkeys (Saimiri sciureus). Treatment initiation at the onset of clinical signs reduced virus shedding, which may support outbreak control. Results show that this clinical candidate has the potential to alleviate clinical measles and augment measles virus eradication.

scholarly journals Design of a Small-Molecule Entry Inhibitor with Activity against Primary Measles Virus Strains

2005 ◽  
Vol 49 (9) ◽  
pp. 3755-3761 ◽  
Author(s):  
Richard K. Plemper ◽  
Joshua Doyle ◽  
Aiming Sun ◽  
Andrew Prussia ◽  
Li-Ting Cheng ◽  
...  
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Half Life ◽  
Measles Virus ◽  
Vaccine Coverage ◽  
Developed Countries ◽  
Structural Basis ◽  
Strong Activity ◽  
Coverage Rates ◽  
Measles Outbreaks

ABSTRACT The incidence of measles virus (MV) infection has been significantly reduced in many nations through extensive vaccination; however, the virus still causes significant morbidity and mortality in developing countries. Measles outbreaks also occur in some developed countries that have failed to maintain high vaccine coverage rates. While vaccination is essential in preventing the spread of measles, case management would greatly benefit from the use of therapeutic agents to lower morbidity. Thus, the development of new therapeutic strategies is desirable. We previously reported the generation of a panel of small-molecule MV entry inhibitors. Here we show that our initial lead compound, although providing proof of concept for our approach, has a short half-life (<16 h) under physiological conditions. In order to combine potent antiviral activity with increased compound stability, a targeted library of candidate molecules designed on the structural basis of the first lead has been synthesized and tested against MV. We have identified an improved lead with low toxicity and high stability (half-life ≫ 16 h) that prevents viral entry and hence infection. This compound shows high MV specificity and strong activity (50% inhibitory concentration = 0.6 to 3.0 μM, depending on the MV genotype) against a panel of wild-type MV strains representative of viruses that are currently endemic in the field.

MEASLES VIRUS ELIMINATION: RESOLVED ISSUES AND FUTURE CHALLENGES

2020 ◽  
pp. 83-88
Author(s):  
Kseniia Artemivna Veklych
Keyword(s):  
Measles Virus ◽  
Disease Outbreaks ◽  
Vaccination Schedule ◽  
Successful Implementation ◽  
Complete Elimination ◽  
Virus Elimination ◽  
Vaccination Programs ◽  
Future Challenges ◽  
The Moment ◽  
Measles Outbreaks

Measles is a highly contagious infectious disease caused by an RNA−containing virus of the family Paramyxoviridae and Morbillivirus genus. The most proper way to stop it is a total vaccination. At the moment, live attenuated strains of the Enders − Schwartz measles virus are used to conduct it. Although they were developed more than 50 years ago, the vaccines in use today are effective enough to create a proper immune protection that can defend against an infection for decades, if the vaccination schedule is followed. The vast majority of measles outbreaks that have been reported in Europe over the last seven years have been caused by a lack of an immune response resulting from the unprecedented coverage of the population with vaccination. The measles outbreak observed in the adult and child population of Ukraine since December 2018 indicates the need and urgency of additional efforts to curb the spread and complete elimination of the measles virus. It has been determined that more than 95 % of the population should be vaccinated to ensure an elimination of measles virus and prevent the disease outbreaks after the virus has been imported from the countries that are still endemic to measles. It is noted that as a result of successful implementation of vaccination programs, the public's attention to measles is diminished even among physicians who sometimes have a rather dubious understanding of the disease symptoms. Ensuring a complete elimination of the measles virus requires the development and implementation of additional laboratory tests for immunity, development and realization of new, more polyvalent vaccines that are more readily accepted by population, increased awareness on safety and necessity of vaccination, as well as regulation. Key words: measles, immunity, elimination, epidemiological control, vaccination.

scholarly journals Protection against the New Equine Influenza Virus Florida Clade I Outbreak Strain Provided by a Whole Inactivated Virus Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 784
Author(s):  
Sylvia Reemers ◽  
Sander van Bommel ◽  
Qi Cao ◽  
David Sutton ◽  
Saskia van de Zande
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Clinical Signs ◽  
Field Strain ◽  
Equine Influenza Virus ◽  
Outbreak Strain ◽  
Virus Shedding ◽  
Equine Influenza ◽  
Vaccine Type ◽  
High Level

Equine influenza virus (EIV) is a major cause of respiratory disease in horses. Vaccination is an effective tool for infection control. Although various EIV vaccines are widely available, major outbreaks occurred in Europe in 2018 involving a new EIV H3N8 FC1 strain. In France, it was reported that both unvaccinated and vaccinated horses were affected despite >80% vaccination coverage and most horses being vaccinated with a vaccine expressing FC1 antigen. This study assessed whether vaccine type, next to antigenic difference between vaccine and field strain, plays a role. Horses were vaccinated with an ISCOMatrix-adjuvanted, whole inactivated virus vaccine (Equilis Prequenza) and experimentally infected with the new FC1 outbreak strain. Serology (HI), clinical signs, and virus shedding were evaluated in vaccinated compared to unvaccinated horses. Results showed a significant reduction in clinical signs and a lack of virus shedding in vaccinated horses compared to unvaccinated controls. From these results, it can be concluded that Equilis Prequenza provides a high level of protection to challenge with the new FC1 outbreak strain. This suggests that, apart from antigenic differences between vaccine and field strain, other aspects of the vaccine may also play an important role in determining field efficacy.

scholarly journals Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators

2021 ◽  
Author(s):  
Gisele Nishiguchi ◽  
Fatemeh Keramatnia ◽  
Jaeki Min ◽  
Yunchao Chang ◽  
Barbara Jonchere ◽  
...  
Keyword(s):  
Small Molecule ◽  
Orally Bioavailable

scholarly journals Antiviral Screen against Canine Distemper Virus-Induced Membrane Fusion Activity

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 128
Author(s):  
Neeta Shrestha ◽  
Flavio M. Gall ◽  
Jonathan Vesin ◽  
Marc Chambon ◽  
Gerardo Turcatti ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Rna Virus ◽  
Preventive Measure ◽  
Close Relative ◽  
Fusion Activity ◽  
Canine Distemper

Canine distemper virus (CDV), a close relative of the human pathogen measles virus (MeV), is an enveloped, negative sense RNA virus that belongs to the genus Morbillivirus and causes severe diseases in dogs and other carnivores. Although the vaccination is available as a preventive measure against the disease, the occasional vaccination failure highlights the importance of therapeutic alternatives such as antivirals against CDV. The morbilliviral cell entry system relies on two interacting envelope glycoproteins: the attachment (H) and fusion (F) proteins. Here, to potentially discover novel entry inhibitors targeting CDV H, F and/or the cognate receptor: signaling lymphocyte activation molecule (SLAM) proteins, we designed a quantitative cell-based fusion assay that matched high-throughput screening (HTS) settings. By screening two libraries of small molecule compounds, we successfully identified two membrane fusion inhibitors (F2736-3056 and F2261-0043). Although both inhibitors exhibited similarities in structure and potency with the small molecule compound 3G (an AS-48 class morbilliviral F-protein inhibitor), F2736-3056 displayed improved efficacy in blocking fusion activity when a 3G-escape variant was employed. Altogether, we present a cell-based fusion assay that can be utilized not only to discover antiviral agents against CDV but also to dissect the mechanism of morbilliviral-mediated cell-binding and cell-to-cell fusion activity.

Discovery of Potent, Orally Bioavailable Small-Molecule Inhibitors of the Human CCR2 Receptor

ChemMedChem ◽  
2008 ◽  
Vol 3 (4) ◽  
pp. 660-669 ◽  
Author(s):  
Julien Doyon ◽  
Erwin Coesemans ◽  
Staf Boeckx ◽  
Mieke Buntinx ◽  
Bart Hermans ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Orally Bioavailable

Small molecule combats measles virus

2014 ◽  
Vol 13 (6) ◽  
pp. 416-417
Author(s):  
Charlotte Harrison
Keyword(s):  
Small Molecule ◽  
Measles Virus

scholarly journals Safety and immunogenicity of a glycoprotein E gene-deleted bovine herpesvirus 1 strain as a candidate vaccine strain

2016 ◽  
Vol 36 (11) ◽  
pp. 1067-1074
Author(s):  
Marcelo Weiss ◽  
◽  
Deniz Anziliero ◽  
Mathias Martins ◽  
Rudi Weiblen ◽  
...  
Keyword(s):  
Acute Infection ◽  
Clinical Signs ◽  
Bovine Herpesvirus ◽  
Elisa Test ◽  
Bovine Herpesvirus 1 ◽  
Glycoprotein E ◽  
Virus Shedding ◽  
Group I ◽  
Virus Dose ◽  
Herpesvirus 1

ABSTRACT: A glycoprotein E-deleted Brazilian bovine herpesvirus 1 (BoHV-1gEΔ) was tested regarding to safety and immunogenicity. Intramuscular inoculation of young calves with a high virus dose did not result in clinical signs or virus shedding during acute infection or after dexamethasone administration. Calves vaccinated once IM (group I) or subcutaneously (group II) with live BoHV-1gEΔ or twice with inactivated virus plus aluminum hydroxide (group IV) or Montanide™ (group V) developed VN titers of 2 to 8 (GMT:2); 2 to 4 (GMT:1.65); 2 to 16 (GMT:2.45) and 2 to 128 (GMT:3.9), respectively. All BoHV-1gEΔ vaccinated calves remained negative in an anti-gE ELISA. Lastly, six young calves vaccinated with live BoHV-1gEΔ and subsequently challenged with a virulent BoHV-1 strain shed less virus and developed only mild and transient nasal signs comparing to unvaccinated calves. Thus, the recombinant BoHV-1gEΔ is safe and immunogenic for calves and allows for serological differentiation by a gE-ELISA test.

scholarly journals Genetic Analysis of the Measles Virus From the Outbreaks in South Korea, 2019

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeong-Min Kim ◽  
Sehee Park ◽  
Sujin Kim ◽  
Kye Ryeong Park ◽  
Jin-Sook Wang ◽  
...  
Keyword(s):  
Health Care ◽  
Genetic Analysis ◽  
Health Care Workers ◽  
Measles Virus ◽  
Genetic Characteristics ◽  
Phylogenetic Clustering ◽  
Care Workers ◽  
H Gene ◽  
Measles Outbreaks ◽  
Clustering Patterns

Three genotypes (B3, D8, and H1) of the measles virus (MeV) have recently caused global outbreaks. In Korea, four measles outbreaks were reported during 2018–2019 and most patients were infants and health care workers in their 20s and 30s. To investigate the genetic characteristics and molecular epidemiology of the outbreaks, we analyzed the sequence of MeVs by targeting the N-450, MF-NCR, and/or H gene regions. Considering their phylogenetic relationships, besides the N-450 and MF-NCR sequences that are commonly used for genotyping MeVs, the MF-NCR-H sequence was related to the dynamics for identifying the transmission of MeVs. Phylogenetic clustering patterns reconstructed from the MF-NCR-H sequence set revealed that genotype D8 caused three of the four outbreaks, while B3 seemed to have induced the fourth outbreak. These results suggest that the MF-NCR-H sequence is useful for rapid confirmation of measles outbreaks and to identify the epidemiological routes of MeVs.

scholarly journals A Brazilian glycoprotein E-negative bovine herpesvirus type 1.2a (BHV-1.2a) mutant is attenuated for cattle and induces protection against wild-type virus challenge

2002 ◽  
Vol 22 (4) ◽  
pp. 135-140 ◽  
Author(s):  
Ana Cláudia Franco ◽  
Fernando Rosado Spilki ◽  
Paulo Augusto Esteves ◽  
Marcelo de Lima ◽  
Rudi Weiblen ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Bovine Herpesvirus ◽  
Vaccine Virus ◽  
Parental Virus ◽  
Wild Type Virus ◽  
Wild Type ◽  
Glycoprotein E ◽  
Virus Shedding ◽  
Virus Challenge ◽  
Herpesvirus Type

The authors previously reported the construction of a glycoprotein E-deleted (gE-) mutant of bovine herpesvirus type 1.2a (BHV-1.2a). This mutant, 265gE-, was designed as a vaccinal strain for differential vaccines, allowing the distinction between vaccinated and naturally infected cattle. In order to determine the safety and efficacy of this candidate vaccine virus, a group of calves was inoculated with 265gE-. The virus was detected in secretions of inoculated calves to lower titres and for a shorter period than the parental virus inoculated in control calves. Twenty one days after inoculation, the calves were challenged with the wild type parental virus. Only mild signs of infection were detected on vaccinated calves, whereas non-vaccinated controls displayed intense rhinotracheitis and shed virus for longer and to higher titres than vaccinated calves. Six months after vaccination, both vaccinated and control groups were subjected to reactivation of potentially latent virus. The mutant 265gE- could not be reactivated from vaccinated calves. The clinical signs observed, following the reactivation of the parental virus, were again much milder on vaccinated than on non-vaccinated calves. Moreover, parental virus shedding was considerably reduced on vaccinated calves at reactivation. In view of its attenuation, immunogenicity and protective effect upon challenge and reactivation with a virulent BHV-1, the mutant 265gE- was shown to be suitable for use as a BHV-1 differential vaccine virus.

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