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.

Epidemiological and molecular assessment of a measles outbreak in a highly vaccinated population of northeast Italy

2011 ◽  
Vol 139 (11) ◽  
pp. 1727-1733 ◽  
Author(s):  
P. D'AGARO ◽  
G. DAL MOLIN ◽  
T. GALLO ◽  
T. ROSSI ◽  
D. SANTON ◽  
...  
Keyword(s):  
Measles Virus ◽  
Vaccine Coverage ◽  
Point Of View ◽  
Mmr Vaccine ◽  
Measles Outbreak ◽  
Northeastern Italy ◽  
Molecular Assessment ◽  
Measles Outbreaks ◽  
The City ◽  
Target Children

SUMMARYTwo distinct measles outbreaks, unrelated from the epidemiological point of view but caused by genetically related strains, occurred in the Friuli Venezia Giulia region of northeastern Italy. Forty-two cases were reported during the period April–May 2008. In the first outbreak the index case was a teacher who introduced the virus into the Pordenone area, involving eight adolescents and young adults. The other concomitant outbreak occurred in the city of Trieste with 33 cases. The containment of the epidemics can be explained by the high MMR vaccine coverage in an area where the first dose was delivered to 93·4% and the second dose to 88·3% of the target children. Phylogenetic analysis of 14 measles virus strains showed that they belonged to a unique D4 genotype indistinguishable from the MVs/Enfield.GBR/14.07 strain, probably introduced from areas (i.e. Piedmont and Germany) where this genotype was present or had recently caused a large epidemic.

scholarly journals Interruption of measles transmission in Gipuzkoa (Basque Country), Spain

2004 ◽  
Vol 9 (5) ◽  
pp. 7-8 ◽  
Author(s):  
G Cilla ◽  
M Basterretxea ◽  
J Artieda ◽  
D Vicente ◽  
E Pérez-Trallero
Keyword(s):  
Vaccination Programme ◽  
Measles Virus ◽  
Vaccine Coverage ◽  
Basque Country ◽  
Measles Vaccine ◽  
Mmr Vaccine ◽  
High Coverage ◽  
Imported Cases ◽  
Measles Vaccination ◽  
Measles Outbreaks

Measles vaccine was introduced in Gipuzkoa (Basque country, Spain) in 1978 and was replaced by the measles, mumps, and rubella (MMR) vaccine for children aged 12-15 months in 1981. A second dose of the MMR vaccine was introduced in 1992. Both doses of the MMR vaccine were well accepted by the population and high coverage was achieved (95% and 91% for the first and second doses respectively for the period 1993-2002). Measles virus circulation was interrupted in the second half of the 1990s: no cases of indigenous measles were notified between 1998 and 2003, and only imported cases have been confirmed during this period. These data indicate that the measles vaccination programme implemented has been effective. Nevertheless, to avoid measles outbreaks following viral introduction, high MMR vaccine coverage levels for the two doses have to be maintained (&gt;95%).

scholarly journals Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics

2021 ◽  
Vol 61 (1) ◽  
pp. 465-493 ◽  
Author(s):  
Hariharan Sivaraman ◽  
Shi Yin Er ◽  
Yeu Khai Choong ◽  
Edem Gavor ◽  
J. Sivaraman
Keyword(s):  
Small Molecule ◽  
Receptor Binding ◽  
Viral Entry ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Structural Basis ◽  
Virus Receptor ◽  
Fusion Inhibitors ◽  
Human Coronaviruses ◽  
Transmembrane Serine Protease

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host–pathogen interactions, specifically virus–receptor binding. An in-depth understanding of the virus–receptor binding mechanism is a prerequisite for the discovery of vaccines, antibodies, and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review, we discuss the viral entry mechanism, the known structural aspects of virus–receptor interactions (SARS-CoV-2 S/humanACE2, SARS-CoV S/humanACE2, and MERS-CoV S/humanDPP4), the key protein domains and amino acid residues involved in binding, and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically, we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors, nafamostat mesylate and camostat mesylate, as well as two novel potent fusion inhibitors and the repurposed Ebola drug, remdesivir, which is specific to RNA-dependent RNA polymerase, against human coronaviruses, including SARS-CoV-2.

scholarly journals Characterisation of measles after the introduction of the combined measles-mumps-rubella (MMR) vaccine in 2004 with focus on the laboratory data, 2016 to 2019 outbreak, Romania

2019 ◽  
Vol 24 (29) ◽  
Author(s):  
Mihaela Lazar ◽  
Aurora Stănescu ◽  
Ana Raquel Penedos ◽  
Adriana Pistol
Keyword(s):  
Measles Virus ◽  
Vaccine Coverage ◽  
Laboratory Data ◽  
Molecular Data ◽  
Control Measures ◽  
Mmr Vaccine ◽  
Incidence And Mortality ◽  
Multiple Virus ◽  
Current Outbreak ◽  
Measles Outbreaks

Background Since January 2016, a resurgence of measles in Romania has led to the third measles epidemic in the past 12 years; 64 deaths have been confirmed so far–the highest number of measles-related deaths since the measles-mumps-rubella (MMR) vaccine was introduced in 2004. Aim To provide an overview on the characterisation on measles in Romania after the introduction of the MMR vaccine with focus on the current outbreak, laboratory and molecular analysis. Methods We performed an analysis of measles incidence and mortality after the introduction of MMR vaccination and a retrospective study using serological and molecular data in three consecutive outbreaks with focus on the current outbreak. Results In the current outbreak, 17,533 measles cases were notified to the national surveillance system, 93% were unvaccinated. Measles virus was isolated from 429 samples and 283 were genotyped. Genotype B3 was predominant (n = 269) and sporadic measles cases associated with D8 genotype (n = 9) were also observed; genotype D4 and D8 were identified in the previous two measles outbreaks. The detection of several distinct measles virus B3 genotypes suggests multiple virus importations to Romania. Conclusion The current outbreak is a consequence of insufficient vaccine coverage. Control measures were implemented to improve uptake of MMR vaccine, including administering the first MMR dose at a younger age (9–11 months) and offering catch-up vaccination to children that have not followed the recommended dosing schedule. More measures are needed to improve the surveillance performance and to achieve high routine MMR vaccination coverage.

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.

HIV-associated sub-acute sclerosing panencephalitis – an emerging threat?

2017 ◽  
Vol 28 (9) ◽  
pp. 937-939 ◽  
Author(s):  
Abi Manesh ◽  
Mahesh Moorthy ◽  
Rini Bandopadhyay ◽  
Priscilla Rupali
Keyword(s):  
Young Adult ◽  
Antiretroviral Therapy ◽  
Virus Infection ◽  
Measles Virus ◽  
Vaccine Coverage ◽  
Paediatric Hiv ◽  
Waning Immunity ◽  
Measles Outbreaks

Earlier age of measles virus infection predisposes to development of sub-acute sclerosing panencephalitis (SSPE) and this risk is heightened in HIV-infected children. We describe a HIV-infected young adult on antiretroviral therapy, presenting with a non-classical, fulminant form of SSPE to highlight the unpredictable nature of measles presentation. The recent spate of measles outbreaks due to virus introduction in populations with sub-optimal vaccine coverage or waning immunity and co-existing paediatric HIV cohorts is a cause for concern.

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.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

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