Rhinoviruses

Drugs against the common cold may be designed from the structure of rhinovirus... 

Rossmann suggested that the canyons form the binding site for the rhi-novirus receptor on the surface of the host cells. The receptor for the major group of rhinoviruses is an adhesion protein known as lCAM-1. Cryoelectron microscopic studies have since shown that ICAM-1 indeed binds at the canyon site. Such electron micrographs of single virus particles have a low resolution and details are not visible. However, it is possible to model components, whose structure is known to high resolution, into the electron microscope pictures and in this way obtain rather detailed information, an approach pioneered in studies of muscle proteins as described in Chapter 14. 

Picornaviruses construct their shells from 60 copies each of three different polypeptide chains. These 180 subunits are arranged within the shell in a manner very similar to the 180 identical subunits of bushy stunt virus. In some picornaviruses there are protrusions around the fivefold axes, which are surrounded by deep "canyons." In rhinoviruses, the canyons form the virus s attachment site for protein receptors on the surface of the host cells, and they are adjacent to cavities that bind antiviral drugs. 

Badger, J., et al. Structural analysis of a series of antiviral agents complexed with rhinovirus 14. Proc. Natl. Acad. Sci USA 35 3304-3308, 1988. 

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

Enteroviruses separated from rhinoviruses by acid lability of the latter... 

In the area of medicinal chemistry, Haemers and coworkers synthesized a series of 4 -hydroxy-3-methoxyflavones that exhibited antiviral activity against poliomyelitis and rhinoviruses. A representative number of compounds is shown below. First, O-hydroxyacetophenones 61 were converted to the corresponding flavones 64 using standard conditions in yields of 74-92%. Cleavage of the benzyloxy groups of 64 was then achieved under acidic conditions to deliver the requisite flavones 65. 

Rhinoviruses, which represent the single major cause of common cold, belong to the family of picornavimses that harbors many medically relevant pathogens. Inhibitors of the 3C protease, a cysteine protease, have shown good antiviral potential. Several classes of compounds were designed based on the known substrate specificity of the enzyme. Mechanism-based, irreversible Michael-acceptors were shown to be both potent inhibitors of the purified enzyme and to have antiviral activity in infected cells. 

Poiiovirus Rhinoviruses Coronavi ruses West-Niie-Virus ... 

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. 

Rhinoviruses cause a significant fraction of the common colds suffered by the human population. However, members of the Rhinovirus genus (Picomaviridae family) include 100 different serotypes that infect humans, making a vaccine strategy impractical. Thus, alternative strategies are needed to intervene in these non-life-threatening but inconvenient infections. 

Rhinovirus, like poliovirus, synthesizes a large precursor protein from which all of the mature viral proteins are generated. Two viral proteases are involved in these cleavages 2A protease cleaves the polyprotein precursor at its own N terminus, while the 3C protease is responsible for additional cleavage events to generate the mature viral proteins. Both proteases can release themselves from the polyprotein precursor. Cleavage by 3C occurs between Gln/Gly, but flanking sequences affect efficiency (reviewed in Racaniello 2001). 

Structural analysis of the rhinovirus and the hepatitis A virus 3C proteases (Allaire et al. 1994 Matthews et al. 1994) confirmed earlier predictions that the picomavirus 3C proteases are similar to chymotrypsin-Uke serine proteases in their fold. An important difference is that the serine nucleophile of serine proteases is replaced with a cysteine however, the 3C protease is stracturally distinct from the eukaryotic cysteine protease class of enzymes. 

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... 

Partaledis JA, Yamaguchi K, Tisdale M, Blair EE, Falcione C, Maschera B, Myers RE, Pazhanisamy S, Futer O, CuHinan AB et al (1995) In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydrox-yethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J Virol 69 5228-5235 Patick AK (2006) Rhinovirus chemotherapy. Antiviral Res 71 391-396... 

PhUlpotts RJ, Higgins PG, WUlman JS, Tyrrell DA, Freestone DS, Shepherd WM (1984) Intranasal lymphoblastoid interferon ( WeUferon ) prophylaxis against rhinovirus and influenza virus in volunteers. J Interferon Res 4 535-541... 

Hewson CA, Jardine A. Edwards MR. Laza-Stanca V, Johnston SL Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol 2005 79 12273-12279. 

Rhinoviruses Naked icosahedra 30 nm in diameter The common cold viruses there are over 100 antigenioally distinct types, hence the diffiouity in preparing effective vaccines. The virus is shed copiousiy in watery nasai secretions... 

Potentially, interferon is an ideal anhviral agent in that it acts on many different vimses and is not toxic to host cells. However, the exploitation of this agent in the treatment of viral infechons has been delayed by a number of factors. For example, it has proved to be species-specific and interferons raised in animal sources offered little protechon to human cells. Human interferon is thus needed for the treatment of human infechons and the produehon and purificahon of human interferon on a large scale has proved difficult. The inserhon of human genes for interferon into E. coli has resolved the produehon problems (Chapter 24). Clinical trials have demonstrated that interferon prevents rhinovirus infeehon and has a beneficial effect in herpes, cytomegalovims and hepahtis B vims infechons. 

The structure/activity relationships for the methisazone, 3a, derivatives against adenoviruses and poxviruses have been shown to be similar [78]. Pearson and Zimmerman [79] demonstrated that all three types of polioviruses are inhibited by 2-acetylpyridine JV-dibutylthiosemicarbazone, which is similar to 3a, by blocking viral RNA synthesis. A 3-substituted triazinoindole derivative of isatin was effective against several strains of rhinovirus in tissue culture the mechanism of action is unknown [80]. 

Viruses are a common cause of CAP in children (-65%) and much less common in adults ( 15%).8 Viruses often associated with pneumonia in adults include influenza A and B and adenoviruses, whereas less common causes include rhinoviruses, enteroviruses, cytomegalovirus, varicella-zoster virus, herpes simplex virus, and others. In children, viral pneumonia is caused more commonly by respiratory syncyntial virus, influenza A virus, and parainfluenza virus. The viruses associated with CAP in adults are much less common causes of pneumonia in children. 

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