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Chapter 18 : Development of Antiviral Agents for Picornavirus Infections

Authors: John O'Connell1, Randi Albin1, Deborah Blum1, Paul Grint1, Jerome Schwartz1
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Affiliations: 1: Departments of Antiviral Chemotherapy and Clinical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033.
Content Type: Monograph
Publication Year: 1995

Category: Clinical Microbiology; Viruses and Viral Pathogenesis

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Abstract:

The discovery and development of antiviral agents for the treatment of picornavirus infections have been the focus of extensive research for more than 50 years. This chapter discusses the pharmaceutical advantages of newer molecules with respect to drug development. In reviewing the historical progression toward potent picornavirus antiviral agents, two classes of inhibitors (interferon and capsid-binding molecules) stand out as having demonstrated efficacy in clinical trials of picornavirus infections. This chapter reviews the activities of these agents and their corresponding clinical data. A discussion of problems in the further development of antipicornavirus agents is also presented in this chapter. Experimental approaches to modulation of enteroviral infections have included research on chemotherapy, monoclonal antibodies, vaccines, interferons, and capsid-binding agents. Several factors appear to correlate with the abilities of a compound to bind to the drugbinding pocket and to manifest antiviral activity. Examples of the potential influence of these parameters on compound binding and antiviral activity are discussed in this chapter. The chapter talks about mechanism of viral inhibition by capsid-binding molecules, preclinical biology of capsidbinding molecules, and clinical studies with capsidbinding molecules. The majority of molecules studied have limited solubility in aqueous environments. Significant progress has been made in the discovery and development of chemotherapeutic agents for picornaviruses.

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18

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Development of Antiviral Agents for Picornavirus Infections
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Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
/content/10.1128/9781555818326.chap18.fig18-1
FIGURE 1

Induction of 2′,5′-adenylate synthetase system by viral infection. Infection of HeLa cells with encephalomyocarditis (EMC) virus results in formation of double-stranded RNA (dsRNA), which has a dual activity: it activates 2',5'-adenylate synthetase and results in the production of interferon. The appearance of 2'5'(A)n induces RNase L, which degrades incoming viral RNA, probably at the poly(A) 3' terminus. Interferon induces 2',5'-adenyIate synthetase in adjacent cells, inducing the cascade, which then prevents incoming EMC virus from replicating in the adjacent cell. The figure is based on studies by Hearl and Johnston ( ) and Gribaudo et al. ( ).

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10.1128/9781555818326/fig18-1.gif
Image of FIGURE 1
FIGURE 1

Induction of 2′,5′-adenylate synthetase system by viral infection. Infection of HeLa cells with encephalomyocarditis (EMC) virus results in formation of double-stranded RNA (dsRNA), which has a dual activity: it activates 2',5'-adenylate synthetase and results in the production of interferon. The appearance of 2'5'(A)n induces RNase L, which degrades incoming viral RNA, probably at the poly(A) 3' terminus. Interferon induces 2',5'-adenyIate synthetase in adjacent cells, inducing the cascade, which then prevents incoming EMC virus from replicating in the adjacent cell. The figure is based on studies by Hearl and Johnston ( ) and Gribaudo et al. ( ).

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
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FIGURE 2

Chemical structures of representative picornavirus capsid binding inhibitors

10.1128/9781555818326/fig18-2_thmb.gif
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Image of FIGURE 2
FIGURE 2

Chemical structures of representative picornavirus capsid binding inhibitors

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
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FIGURE 3

Binding of SCH 38057 to HRV14. Atoms of SCH 38057 are indicated by colored spheres. The main chain of VPl is indicated by ribbons. Conformational changes induced by SCH 38057 are indicated as follows: blue, no significant conformational shifts in these residues; yellow, main chain shifts less than 0.5 Å (0.05 nm); pink, main chain shifts less than 1.0 Å (0.1 nm); red, main chain shifts more than 1.0 Å (0.1 nm). Selected pocket residues are indicated in white. (From Zhang et al., [ ].)

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10.1128/9781555818326/fig18-3.gif
Image of FIGURE 3
FIGURE 3

Binding of SCH 38057 to HRV14. Atoms of SCH 38057 are indicated by colored spheres. The main chain of VPl is indicated by ribbons. Conformational changes induced by SCH 38057 are indicated as follows: blue, no significant conformational shifts in these residues; yellow, main chain shifts less than 0.5 Å (0.05 nm); pink, main chain shifts less than 1.0 Å (0.1 nm); red, main chain shifts more than 1.0 Å (0.1 nm). Selected pocket residues are indicated in white. (From Zhang et al., [ ].)

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
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FIGURE 4

Schematic diagram of SCH 38057 in the hydrophobic pocket of HRV14 VP1. SCH 38057 is located in the innermost end of the pocket and leaves a large open space near the entrance of the pocket. This is in contrast to WIN compounds ( ) andjanssen R61837 ( ), which occupy the space nearest the entrance and leave open space in the innermost portion of the pocket. (Derived from Zhang et al.[ ].)

10.1128/9781555818326/fig18-4_thmb.gif
10.1128/9781555818326/fig18-4.gif
Image of FIGURE 4
FIGURE 4

Schematic diagram of SCH 38057 in the hydrophobic pocket of HRV14 VP1. SCH 38057 is located in the innermost end of the pocket and leaves a large open space near the entrance of the pocket. This is in contrast to WIN compounds ( ) andjanssen R61837 ( ), which occupy the space nearest the entrance and leave open space in the innermost portion of the pocket. (Derived from Zhang et al.[ ].)

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
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FIGURE 5

Comparison of conformational shifts in the HRV14 VP1 region upon binding of SCH 38057 andWIN 51711. Displacements of C-alpha atoms relative to the native HRV14 coordinates are shown as dots. Changes in the βC and βD strands are similar in the two compounds. However, changes in the βD, βF, and βG strands in the SCH 38057 complex are not reported in theWIN 51711 studies with HRV14. (Derived from Zhang et al. [ ].)

10.1128/9781555818326/fig18-5_thmb.gif
10.1128/9781555818326/fig18-5.gif
Image of FIGURE 5
FIGURE 5

Comparison of conformational shifts in the HRV14 VP1 region upon binding of SCH 38057 andWIN 51711. Displacements of C-alpha atoms relative to the native HRV14 coordinates are shown as dots. Changes in the βC and βD strands are similar in the two compounds. However, changes in the βD, βF, and βG strands in the SCH 38057 complex are not reported in theWIN 51711 studies with HRV14. (Derived from Zhang et al. [ ].)

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
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Tables

Development of Antiviral Agents for Picornavirus Infections
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Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
/content/10.1128/9781555818326.chap18.tab18-1
TABLE 1

Comparison of amino acids in the drug-binding pockets of different picornaviruses

10.1128/9781555818326/tab18-1_thmb.gif
10.1128/9781555818326/tab18-1.gif
Generic image for table
TABLE 1

Comparison of amino acids in the drug-binding pockets of different picornaviruses

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18
/content/10.1128/9781555818326.chap18.tab18-2
TABLE 2

Conformational changes induced in main chains of HVR14 by capsid-binding antiviral compounds

10.1128/9781555818326/tab18-2_thmb.gif
10.1128/9781555818326/tab18-2.gif
Generic image for table
TABLE 2

Conformational changes induced in main chains of HVR14 by capsid-binding antiviral compounds

Citation: O'Connell J, Albin R, Blum D, Grint P, Schwartz J. 1995. Development of Antiviral Agents for Picornavirus Infections, p 419-434. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch18

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