Receptors for Rhinoviruses

Because the cytoplasmic domain of ICAM-1 lacks typical signal sequences that mediate endocytosis, ICAM-1 may not directly regulate virus internalization. This notion is supported by experiments in which 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). 

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Staunton, D.E., Merluzzi, V.J., Rothlein, R., Barton, R., Marlin, S.D., Springer, T.A., 1989. A cell adhesion molecule, lCAM-1, is the major surface receptor for rhinoviruses. Cell 56, 849-853. 

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. 

Figure 7-15 (A) Schematic diagram of the icosahedral shell of a human rhinovirus showing the arrangement of the three subunits VP1, VP2, and VP3, each present as 60 copies. (B) Stereoscopic view of an image of the virus "decorated" by the binding of two immunoglobulinlike domains of the intercellular adhesion molecule ICAM-1, a natural receptor for the virus.

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... 

Virus receptors are defined as surface structures that allow viruses to attach to the cell and to initiate an infection. Distinct surface proteins have been identified as virus receptors, e.g., CD4 for HIV and ICAM-1 for rhinoviruses. The actual domain of the protein that is recognized by the virus is designated receptor determinant. Applying this terminology to viruses that attach to any derivatives of neuraminic acid on the cell surface, sialic acid is designated as receptor determinant. As sialic acids are present on many glycoproteins and glycolipids, different surface molecules may serve as receptors for these viruses. 

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. 

More recently attempts to generate highly selective quiescent affinity labels have been made for a number of protease and kinase targets. As examples, inhibitors of the Rhinovirus 3C protease (Mathews et al 1999) and of the epidermal growth factor receptors (Boschelli, 2002), both incorporating Michael acceptors to covalently inactivate cysteine residues in their target enzymes (Lowry and Richardson, 1981 Figure 8.6), have entered human clinical trials for the treatment of rhinovirus infection and cancer, respectively. 

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]. 

Colonno RJ, Condra JH, Mizutani S, Callahan PL, Davies ME, Murcko MA. Evidence for direct involvement of the rhinovirus canyon in receptor binding. Proc Natl Acad Sci USA 1988 ... 

Hodits, R. A., Nimpf, J., Pfistermueller, D. M., Hiesberger, T., Schneider, W. J., Vaughan, T.J., Johnson, K. S., Haumer, M., Kuechler, E., Winter, G., etal. (1995). An antibody fragment from a phage display library competes for ligand binding to the low density lipoprotein receptor family and inhibits rhinovirus infection. J. Biol. Chem., 270(41), 24078-24085. 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

The picornavirus family, which includes rhinovirus, poliovirus, and foot-and-mouth disease virus, has provided the test bed for structural studies on virus-antibody and virus-receptor complexes. The crystal structure of human rhinovirus 14 (HRV14) revealed a canyon encircling the 5-fold... 

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...

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