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

Abstract

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.

Figure 1

Organization of the enterovirus genome (top) and main functions of nonstructural proteins (bottom). The protein coding region of the enterovirus genome is flanked by the 5′and 3′untranslated region (UTR). A small virus protein (VPg) is covalently linked to the 5′UTR containing the internal ribosome entry site (IRES). The 3′UTR has a poly(A) tail like cellular messenger RNAs.

Figure 2

Chemical structures of selected capsid‐binding agents with potent anti‐HRV activity.

Figure 3

Chemical structures of most active inhibitors of 2A and 3C protease of HRV.

Figure 4

Chemical structures of most active inhibitors of HRV replication.

Figure 5

Chemical structures of natural anti‐HRV compounds.