Medical Pharmacology Chapter 36:  Antiviral Drugs

• Viral Capsid Assembly:

  • Formation of viral capsids depends on highly reproducible assembly of many protein subunits (60 to thousands).¹

    • "HSV encapsidation"

      Attribution: PipettingPit "HSV encapidation" https://www.youtube.com/watch?v=kpPO9SLB95c&list=PLMWp6GrFUVuKK9DkkWF8g8SZmIyqemsC_&index=30 PipettingPit YouTube Channel:  https://www.youtube.com/channel/UCD0zzp5zpgBof2_vfCPw6RA

    • These reproducible assemblies occur under different conditions and do so as a result of  kinetic and thermodynamic optimization.

       

      • "Stochastic Dynamics of Virus Capsid Formation:  Hierachical Self-Assembly"

        Attribution:  Baschek JE Stochastic Dynamics of Virus Capsid Formation:  Direct versus Hierarchical Self-Assembly https://www.youtube.com/watch?v=puK--gvqpXs (12/2012) BMC YouTube Channel:  https://www.youtube.com/user/BioMedCentral/videos

    • Such assembly and capsid component features that support it may be important in development of antiviral drugs which inhibit capsid assembly or disassembly.¹

  • Characteristics of capsid assembly depend both on features of the final structure and on the viral genome.² 

    • Capsids characteristic of many small, icosahedral positive-strand RNA viruses assemble around viral RNA.

    • During this process the viral RNA is compacted.

      • Capsid subunits of some viruses depend on genomic RNA to assemble although others can form shells without RNA.

    • In the case of viruses which utilize double-stranded RNA or DNA nucleic acid coiling is often observed.

    • Polyomaviruses and papillomaviruses exhibit capsids that assemble around double-stranded DNA pre-wound into nucleosomes facilitated by cellular histones.²

  • Genome packaging depends on specific and varied mechanisms.² 

    • For example, positive-strand, small icosahedral capsid-type RNA viruses utilize capsid protein N-terminal arms to facilitate packaging.²   

      • This arm interacts with a specific sequence on genomic RNA which facilitates packaging.

      • Specific interactions between an RNA sequence containing a "stem-loop" structure have been implicated.

      • The genomic RNA packaging sequence binds to capsid protein subunits during capsid assembly, thereby initiating both capsid assembly and genomic packaging.

        • Most capsid subunits associate with non-specific RNA regions.

          • Encapsidated RNA is very dense i.e. highly condensed.²   

    • Similarly, the molecular mechanism responsible for spooling DNA of herpesviruses into the procapsid exhibits affinity for specific viral DNA packaging sequences.

      • This type of molecular machine is coupled to ATP hydrolysis and is therefore described as energy-dependent.²   

    • One packaging signal that has been described is the Coronavirus packaging signal, a conserved cis-regulatory element (cis-regulatory element: a non-coding DNA region regulating nearby gene transcription)  important in viral genome packaging regulation into the capsid.⁴ 

      •  

        Coronaviruses⁶

        Murphy F Coronaviruses6 "Coronaviruses are a group of viruses that have a halo, or crown-like (corona) appearance when view under an electron microscope. The coronavirus is now recognized as the etiologic agent of the 2003 SARS outbreak. Additional specimens are being testing to learn more about this coronvirus and its etiologic link with Severe Acute Respiratory Syndrome."6

      • Coronavirus is a positive-sense single-stranded RNA virus.

      • A region of the viral genome (190 base pairs) has been described as interacting with a viral envelope protein (protein M) thereby enabling viral RNA to be packaged into virions.⁴

    • In a murine coronavirus mouse hepatitis virus (MHV) model system, a short cis-acting MHV RNA packaging signal was shown as both necessary and sufficient for packaging RNA into MHV particles.⁵  

      • The study demonstrated that only RNA which interacted selectively with M protein was efficiently packaged into MHV particles and that the packaging signal mediated this specific interaction.

      •  Accordingly, both specificity and selectivity of RNA packaging into virions was directly associated with a viral envelope protein in a known viral RNA packaging signal.⁵

    •  

      Coronavirus Reptication (capsidation circled in red)⁷

      OrreBot The infection cycle of corona virus7 http://www.en.wikipedia.org/wiki/Corona_virus#mediaviewer/File:Coronavirus_replication.png