Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors

Pevear, D.C.; Fancher, M J; Felock, Peter J.; Rossmann, Michael G.; Miller, Mark Steven; Diana, Guy D.; Treasurywala, Adi M.; McKinlay, Mark A.; Dutko, Frank J.

doi:10.1128/jvi.63.5.2002-2007.1989

Cited by 188 publications

(69 citation statements)

References 13 publications

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“…Underneath the canyon is an interior hydrophobic "pocket", formed by the beta-barrel of the VPI capsid protein. Most capsid binding drugs bind within this pocket, which results in inhibition of uncoating and, for some strains of HRV, reduced binding to the receptor (Smith et al, 1986;Pevear et al, 1989). Administration of the novel, orally absorbed capsid-binding drug, pleconaril, beginning within 24 h of symptom development, was shown to reduce symptom duration and severity in naturally-acquired HRV infections .…”

Section: Approaches Based On Viral Inhibition or Blockade Of Pathogenmentioning

confidence: 99%

Virus-induced modulation of lower airway diseases: Pathogenesis and pharmacologic approaches to treatment

Leigh

Proud

2015

Pharmacology & Therapeutics

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Uncomplicated upper respiratory viral infections are the most common cause of days lost from work and school and exert a major economic burden. In susceptible individuals, however, common respiratory viruses, particularly human rhinoviruses, also can have a major impact on diseases that involve the lower airways, including asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). Respiratory virus-induced wheezing illnesses in early life are a significant risk factor for the subsequent development of asthma, and virus infections may also play a role in the development and progression of airway remodeling in asthma. It is clear that upper respiratory tract virus infections can spread to the lower airway and trigger acute attacks of asthma, COPD or CF. These exacerbations can be life-threatening, and exert an enormous burden on health care systems. In recent years we have gained new insights into the mechanisms by which respiratory viruses may induce acute exacerbations of lower airway diseases, as well as into host defense pathways that may regulate the outcomes to viral infections. In the current article we review the role of viruses in lower airway diseases, including our current understanding on pathways by which they may cause remodeling and trigger acute exacerbations. We also review the efficacy of current and emerging therapies used to treat these lower airway diseases on the outcomes due to viral infection, and discuss alternative therapeutic approaches for the management of virus-induced airway inflammation.

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Section: Approaches Based On Viral Inhibition or Blockade Of Pathogenmentioning

confidence: 99%

Virus-induced modulation of lower airway diseases: Pathogenesis and pharmacologic approaches to treatment

Leigh

Proud

2015

Pharmacology & Therapeutics

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“…The canyon, comprised mostly of VP1 and VP3 residues, encircles the point at which five protomers come together to create the 5-fold axis (Rossmann, 1994;Rossmann et al, 1985). The canyon rim restricts entry of the 3.5 nm Fab portion of antibody molecules, evident in the conservation of the canyon floor which is sequestered away from immune pressures and provides a safe harbour for receptor contact among the majority of known HRV strains (Rossmann et al, 1985;Pevear et al, 1989). (e) Top view ribbon depiction of five protomers comprising a viral pentamer and their relative orientation.…”

Section: Classification Schemes: Strains Types Groups and Speciesmentioning

confidence: 99%

Human rhinoviruses: The cold wars resume

Mackay

2008

Journal of Clinical Virology

100

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“…In doing so, capsid-binders induce conformational changes of the canyon of HRV-3 and HRV-14, hinder virus-receptor interactions, and prevent attachment to host cells. 105,175,[177][178][179] In addition, uncoating of both HRV serotypes was shown to be inhibited as a result of a potential loss of flexibility of the viral capsid after drug binding. In contrast to HRV-3 and HRV-14, capsid-binding compounds did not prevent attachment of HRV-1A.…”

Section: A Options To Prevent Virus Attachment And/or Uncoatingmentioning

confidence: 99%

The human rhinovirus: human‐pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery

Rollinger

Schmidtke

2010

Medicinal Research Reviews

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As the major etiological agent of the common cold, human rhinoviruses (HRV) cause millions of lost working and school days annually. Moreover, clinical studies proved an association between harmless upper respiratory tract infections and more severe diseases e.g. sinusitis, asthma, and chronic obstructive pulmonary disease. Both the medicinal and socio-economic impact of HRV infections and the lack of antiviral drugs substantiate the need for intensive antiviral research. A common structural feature of the approximately 100 HRV serotypes is the icosahedrally shaped capsid formed by 60 identical copies of viral capsid proteins VP1-4. The capsid protects the single-stranded, positive sense RNA genome of about 7,400 bases in length. Both structural as well as nonstructural proteins produced during the viral life cycle have been identified as potential targets for blocking viral replication at the step of attachment, entry, uncoating, RNA and protein synthesis by synthetic or natural compounds. Moreover, interferon and phytoceuticals were shown to protect host cells. Most of the known inhibitors of HRV replication were discovered as a result of empirical or semi-empirical screening in cell culture. Structure-activity relationship studies are used for hit optimization and lead structure discovery. The increasing structural insight and molecular understanding of viral proteins on the one hand and the advent of innovative computer-assisted technologies on the other hand have facilitated a rationalized access for the discovery of small chemical entities with antirhinoviral (anti-HRV) activity. This review will (i) summarize existing structural knowledge about HRV, (ii) focus on mechanisms of anti-HRV agents from synthetic and natural origin, and (iii) demonstrate strategies for efficient lead structure discovery.

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Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors

Abstract: A series of eight antiviral compounds complexed with human rhinovirus 14 (HRV-14) were previously shown to displace segments of polypeptide chains in the floor of the "canyon" by as much as 0.45 nm in C-alpha positions from the native conformation (J. Badger, I.

Cited by 188 publications

References 13 publications

Virus-induced modulation of lower airway diseases: Pathogenesis and pharmacologic approaches to treatment

Virus-induced modulation of lower airway diseases: Pathogenesis and pharmacologic approaches to treatment

Human rhinoviruses: The cold wars resume

The human rhinovirus: human‐pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery

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