Rhinoviruses, human

TMS = tetramethylsilane DMB = 2,4 limethQxybenzyl DMSO = dimothyl sulfoxide Ts-Tosyl 

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Badger, J., et al. Three-dimensional structures of drug-resistant mutants of human rhinovirus 14. /. Mol. Biol. 

Smith, T.J., et al. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science 233 1286-1293, 1986. 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

Matthews DA, Smith WW, Ferre RA, Condon B, Budahazi G, Sisson W, Villafranca JE, Janson CA, McElroy HE, Gribskov CL et al (1994) Structure of human rhinovirus 3C protease reveals a trypsin-like polypeptide fold, RNA-binding site, and means for cleaving precursor polyprotein. CeU 77 761-771... 

Matthews DA, Dragovich PS, Webber SE, Fuhrman SA, Patick AK, Zalman LS, Hendrickson TF, Love RA, Prins TJ, Marakovits JT, Zhou R, Tikhe J, Ford CE, Meador JW, Ferre RA, Brown EL, Binford SL, Brothers MA, DeLisle DM, Worland ST (1999) Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes. Proc Natl Acad Sci USA 96 11000-11007... 

In 1985 Dr. Michael Rossmann and his colleagues determined for the first time the three-dimensional structure of a human rhinovirus [15], Their studies, performed with human rhinovirus type 14 (HRV-14), revealed the structure as an eicosahedron consisting of four proteins designated VP1, VP2, VP3, and VP4 forming a protomeric unit, combined to form a fivefold axis of symmetry (Fig. 2). The surface of the capsid... 

Greve JM, Davis G, Meyer AM, et al. The major human rhinovirus receptor is ICAM-1. Cell 1989 56 839-847. 

Uncapher GR, Dewitt CM, Colonno RJ. Human rhinovirus serotype families contain all but one human rhinovirus serotype. Virology 1991 180 814— 817. 

Fox MP, McKinlay MA, Diana GD, Dutko FJ. Binding affinities of structurally related human rhinovirus capsid binding compounds are related to their activities against human rhinovirus type 14. Antimicrob Agents Chemother 1991 30 110-116. 

Pevear DC, Fancher MJ, Felock, et al. Conformational changes in the floor of the human rhinovirus canyon blocks adsorption to Hela cell receptors. J Virol 1989 63 2002-2007. 

Badger, Minor I, Kremer MJ, et al. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Nat Acad Sci USA 1988 85 3304-3308. 

Diana GD, Treasurywala AM, Bailey TR, Oglesby RC, Pevear DC, Dutko FJ. A model for compounds active against human rhinovirus-14 based on X-ray crystallography data. J Med Chem 1989 33 1306-1311. 

Hunt, S. L., Hsuan, J. J., Totty, N., and Jackson, R. J. (1999). Unr, a cellular cytoplasmic RNA-binding protein with five cold-shock domains, is required for internal initiation of translation of human rhinovirus RNA. Genes Dev. 13, 437—448. 

Human rhinovirus type 14 VP1 epitope Epitope display on cowpea mosaic virus in cowpea leaf Immunogenic in rabbits when delivered parenterally. 81... 

Dragovich PS, Webber SE, Babine RE et al (1998) Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. J Med Chem 41 2819-2834... 

The bicyclic 2-pyridone-containing 3CP (human rhinovirus 3C protease) inhibitor 279 displayed improved inhibition properties and exhibited potent antirhinoviral activity in cell culture when tested against a number of different human rhinovirus (HRV) serotypes <2002BML733>. 

Human rhinoviruses (HRV) are members of the Picornaviridae family. The HRVs are classified according to their receptor specificity into members of the major and minor groups. The 87 members of the major-group viruses bind to the intracellular adhesion molecule receptor 1 (ICAM-1), whereas the 12 serotypes of the minor group bind to members of the low-density lipoprotein receptor family (LDLR) [42]. Rhinoviruses cause more than a billion cases of the common cold each year and are also associated with asthma exacerbations [43,44]. Statistically, one encounters one to three infections per year on the average [45]. As a result, rhinoviral infections are responsible for 25 million days of missed work in the USA [46]. 

Utilizing STD NMR experiments we have resolved the binding epitope for one of the WIN compounds, REPLA 394, at atomic resolution [53]. Competitive STD NMR titrations then yielded the dissociation constant. When bound to native human rhinovirus serotype 2 (HRV2), saturation is predominantly transferred to the isoxazole and the benzoic acid residues, whereas the aliphatic linker receives less saturation (Fig. 3). Results reported before [16] are in accordance with the data reported in our study. 

Arnold, E., et al. (1987). Structure determination of a common cold virus, human rhinovirus 14. Acta Crystallogr. A43, 346-361. 

Hewat, E. A. and Blaas, D. (1996). Structure of a neutralizing antibody bound bivalently to human rhinovirus 2. EMBO]. 15,1515-1523. 

Verdaguer, N., et al. (2004). X-ray structure of a minor group human rhinovirus bound to a fragment of its cellular receptor protein. Nat. Struct. Mol. Biol. 11, 429 4. 

Fig. 10 Formation of complexes between human rhinovirus HRV2 and neutralizing monoclonal antibody mAb 8F5 analyzed by CE. A fixed concentration of F1RV2 (15 nM) was incubated with an increasing concentration (indicated in the figure) of mAb 8F5 prior to the CE analysis at room temperature. O-phthalic acid was used as internal standard (IS). (Reprinted with permission from Ref. 34. Copyright 2000 American Chemical Society.)...

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