Rhinovirus group

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. 

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. 

Figure 8.7 Chemical structure of the Rhinovirus 3C protease inactivator AG7088. The shaded box highlights the Michael acceptor group within the compound.

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]. 

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. 

With respect to immobile chiroids, the appropriate symmetries are given by the familiar finite point groups C, (nonaxial), C (monoaxial), Dn (dihedral), T (tetrahedral), 0 (octahedral), and I (icosahedral). Molecules that belong to the first three groups are commonplace molecules with ground-state symmetries T [example tetrakis(trimethylsilyl)silane],39 O (example appoferritin 24-mer),40 and 1 (example human rhinovirus 60-mer),40 are relatively uncommon. 

This theme has been developed by studies of receptor—virus interactions for low-density lipoprotein receptor (LDLR), the receptor for a minor receptor group rhinovirus HRV-2 (Hewat et al, 2000), and the glycolipid globoside bound to human parvovirus (Chipman et al, 1996). Both of these receptors are small and globular and bind at different positions on the viral surface. In the case of LDLR, binding is at a star-shaped dome... 

HRV2 is a member of the minor group of human rhinoviruses. Although all of the rhinoviruses have nearly identical structures, the minor and major groups of rhinoviruses differ in several important aspects. The receptor for the major group is ICAM-1, which binds in the canyon region, whereas the receptor for the minor group is low-density lipoprotein... 

Marlovits, T. G., Abrahamsberg, C., and Blaas, D. (1998). Soluble LDL minireceptors Minimal structure requirements for recognition of minor group human rhinovirus. J. Biol Chem. 273, 33835-33840. 

Mischak, H., Neubauer, C., Kuechler, E., and Blaas, D. (1988). Characteristics of the minor group receptor of human rhinoviruses. Virology 163, 19-25. 

Fig. 8. The two-step binding mechanism proposed for the interaction between ICAM-1 and the m or group rhinoviruses. (A) Step 1 corresponds to the structure observed in the cryo-EM reconstructions of HRV-ICAM-1 complexes. The cryo-EM structure is thought to represent the initial interaction step. (B) Step 2 is hypothesized and involves movement of the receptor and resulting conformational change of the...

Whereas ICAM-1 clearly mediates attachment and infection of the major group of HRVs, the human low-density lipoprotein receptor (LDLR) has been identified as the receptor for the minor group of rhinoviruses, including HRV2 (Hofer et al, 1994). The LDLR appears to mediate internalization of HRV2 via a classic endocytic pathway. Subsequently, the transfer of viral RNA occurs from the endosome/late endosome through a pore in the endosomal membrane (Prchla et al, 1995). 

There is at least one example in the literature (330) in which the calculated affinity difference did not agree with the experimental date [binding of an antiviral agent to human rhinovirus HRV-14 and to a mutant virus in which a valine was mutated to a leucine (Fig. 3.26)J. Here a j8-branched amino acid (Val) was converted into Leu, which lacks the isopropyl side chain adjacent to the peptide backbone besides the addition of a methyl group. 

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