Target Analysis of the Experimental Measles Therapeutic AS-136A

Yoon, Jeong-Joong; Krumm, Stefanie A.; Ndungu, John M.; Hoffman, Vanessa; Bankamp, Bettina; Rota, Paul A.; Sun, Aiming; Snyder, James P.; Plemper, Richard K.

doi:10.1128/aac.00503-09

Cited by 31 publications

(58 citation statements)

References 51 publications

(57 reference statements)

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“…All compounds were dissolved in dimethyl sulfoxide (DMSO) and stored at Ϫ80°C. The previously characterized pan-myxovirus inhibitor JMN3-003 (4), MeV RNA-dependent RNA polymerase (RdRp) inhibitor AS-136A (34), and MeV entry inhibitor AS-48 (35) were synthesized in-house, and their purity was confirmed to be Ͼ95% by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) analysis. The screening library (ChemDiv) was designed to cover a broad chemical space within the boundaries of druglike physical-chemical properties, a molecular weight range of 120 to 500, and best adherence to the Lipinski rule of 5 (36).…”

Section: Methodsmentioning

confidence: 99%

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Yan

Krumm

Sun

et al. 2013

J Virol

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f As we are confronted with an increasing number of emerging and reemerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting of host factors required for virus replication presents a tangible approach toward obtaining novel hits with a broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource efficiency and pan-myxovirus activity as the central developmental parameters, we explored coscreening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired coreplication of both viruses, generated suitable firefly and Renilla luciferase reporter constructs, respectively, and validated the protocol for up to a 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with a broadened antimyxovirus profile, in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broadspectrum lead that does not block viral entry but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof of concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para-and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.

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Section: Methodsmentioning

confidence: 99%

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Yan

Krumm

Sun

et al. 2013

J Virol

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“…A highthroughput screening led to an active compound, which was further chemically improved to achieve the lead compound AS-136A that blocked viral RNA synthesis with IC 50 values of as low as 12 nM, and no detectable cytotoxicity at concentrations below 300 lM [137][138][139]. Adaptation of different MV strains to growth in the presence of this compound identified three candidate hot spots for interaction with AS-136A that are located in conserved domains of the viral L-protein [140]. Recombinant MVs harboring individual resistance mutations showed some delay in the onset of viral growth in vitro suggesting that mutations in these L-protein domains may reduce viral fitness [140].…”

Section: Approaches To a Specific Therapymentioning

confidence: 98%

“…Adaptation of different MV strains to growth in the presence of this compound identified three candidate hot spots for interaction with AS-136A that are located in conserved domains of the viral L-protein [140]. Recombinant MVs harboring individual resistance mutations showed some delay in the onset of viral growth in vitro suggesting that mutations in these L-protein domains may reduce viral fitness [140]. However, these findings also demonstrated that resistance mutations that enable viral escape may well be present or emerge in vivo.…”

Section: Approaches To a Specific Therapymentioning

confidence: 99%

Measles virus infection of the CNS: human disease, animal models, and approaches to therapy

Reuter

Schneider-Schaulies

2010

Med Microbiol Immunol

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Viral infections of the central nervous system(CNS) mostly represent clinically important, often life-threatening complications of systemic viral infections. After acute measles, CNS complications may occur early (acute postinfectious measles encephalitis, APME) or after years of viral persistence (subacute sclerosing panencephalitis, SSPE). In spite of a presumably functional cell-mediated immunity and high antiviral antibody titers, an immunological control of the CNS infection is not achieved in patients suffering from SSPE. There is still no specific therapy for acute complications and persistent MV infections of the CNS. Hamsters, rats, and (genetically unmodified and modified) mice have been used as model systems to study mechanisms of MV-induced CNS infections. Functional CD4+ and CD8+ T cells together with IFN-gamma are required to overcome the infection. With the help of recombinant measles viruses and mice expressing endogenous or transgenic receptors, interesting aspects such as receptor-dependent viral spread and viral determinants of virulence have been investigated. However, many questions concerning the lack of efficient immune control in the CNS are still open. Recent research opened new perspectives using specific antivirals such as short interfering RNA (siRNA) or small molecule inhibitors. Inspite of obvious hurdles, these treatments are the most promising approaches to future therapies.

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“…In many cases, suggested substances were only moderately active, highly cytotoxic, inactive when added to cells post-infection in tissue culture, or the active ingredient remained uncharacterized, eliminating them from consideration for serious development. The three best characterized candidates are morpholino oligomers (77), peptide entry inhibitors (80, 81), and small-molecule allosteric inhibitors of the viral RNA-dependent RNA-polymerase (RdRp) complex (102, 105, 106). Of these, morpholino oligomers showed only intermediate inhibitory activity (5-15 μM active concentration range) in cell culture and effective in vivo delivery is challenging.…”

Section: 5 Measles Management Strategies and Developmental Inhibitomentioning

confidence: 99%

“…This disease profile demands continued spread to sustain the virus in a population, making MeV vulnerable to changes in viral fitness, since even slight reductions in transmission success should render the virus clinically insignificant. For instance, hot spots of viral escape from the lead class of allosteric RdRp inhibitors were identified experimentally and found to locate to regions of the viral L protein that are completely conserved among different MeV genotypes (105). Sequence conservation suggests that these L microdomains are under selective control in vivo , preventing the development of sequence heterogeneity.…”

Section: 6 Measles Therapeutics and Viral Resistancementioning

confidence: 99%

Synergizing vaccinations with therapeutics for measles eradication

Plemper

Hammond

2013

Expert Opinion on Drug Discovery

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Introduction Measles virus is a major human pathogen responsible for approximately 150,000 measles deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence combined with public anxieties about vaccination safety has increased vaccine refusal especially in the European region, which has resulted in measles resurgence in some areas. Areas covered Here, we discuss whether synergizing effective measles therapeutics with vaccination could contribute to solving an endgame conundrum of measles elimination by accelerating the eradication effort. Based on an anticipated use for protection of high-risk contacts of confirmed measles cases through post-exposure prophylaxis, we identify key elements of the desirable drug profile, review current disease management strategies and the state of experimental inhibitor candidates, evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics for the management of persistent viral infection of the CNS. Assuming a post-measles world with waning measles immunity, we contemplate the possible impact of therapeutics on controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles virus. Expert opinion Efficacious therapeutics given for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent patient population dictates the drug profile; the article must be safe and efficacious, orally available, shelf-stable at ambient temperature, and amenable to cost-effective manufacture.

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Target Analysis of the Experimental Measles Therapeutic AS-136A

Cited by 31 publications

References 51 publications

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response

Measles virus infection of the CNS: human disease, animal models, and approaches to therapy

Synergizing vaccinations with therapeutics for measles eradication

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