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Tegument Protein pp150 Sequence-Specific Peptide Blocks Cytomegalovirus Infection
Dipanwita Mitra1, Mohammad H Hasan1, John T Bates1,2
1Department of Microbiology and Immunology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Abstract:
Human cytomegalovirus (HCMV) tegument protein pp150 is essential for the completion of the final steps in virion maturation. Earlier studies indicated that three pp150nt (N-terminal one-third of pp150) conformers cluster on each triplex (Tri1, Tri2A and Tri2B), and extend towards small capsid proteins atop nearby major capsid proteins, forming a net-like layer of tegument densities that enmesh and stabilize HCMV capsids. Based on this atomic detail, we designed several peptides targeting pp150nt. Our data show significant reduction in virus growth upon treatment with one of these peptides (pep-CR2) with an IC50 of 1.33 μM and no significant impact on cell viability. Based on 3D modeling, pep-CR2 specifically interferes with the pp150-capsid binding interface. Cells pre-treated with pep-CR2 and infected with HCMV sequester pp150 in the nucleus, indicating a mechanistic disruption of pp150 loading onto capsids and subsequent nuclear egress. Furthermore, pep-CR2 effectively inhibits mouse cytomegalovirus (MCMV) infection in cell culture, paving the way for future animal testing. Combined, these results indicate that CR2 of pp150 is amenable to targeting by a peptide inhibitor, and can be developed into an effective antiviral.
Insights
A novel peptide inhibitor, pep-CR2, effectively targets human cytomegalovirus (HCMV) protein pp150, significantly reducing viral growth by disrupting capsid binding and nuclear egress. This peptide shows promise as a potential antiviral therapy.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Human cytomegalovirus (HCMV) tegument protein pp150 is crucial for viral maturation.
- Previous research identified specific structural conformers of the pp150 N-terminus (pp150nt) involved in capsid stabilization.
Purpose of the Study:
- To design and evaluate peptide inhibitors targeting the pp150nt-capsid interaction.
- To investigate the antiviral efficacy and mechanism of action of novel pp150nt-targeting peptides.
Main Methods:
- Peptide design based on atomic-level structural data of pp150nt.
- In vitro antiviral assays to determine efficacy (IC50) and cell viability.
- 3D modeling to predict peptide-target interactions.
- Cell-based assays to study viral protein localization and nuclear egress.
Main Results:
- Peptide pep-CR2 demonstrated significant HCMV growth inhibition with an IC50 of 1.33 μM and no observed cytotoxicity.
- 3D modeling indicated pep-CR2 specifically disrupts the pp150-capsid binding interface.
- Pre-treatment with pep-CR2 led to nuclear sequestration of pp150, inhibiting capsid loading and nuclear egress.
- Pep-CR2 also showed inhibitory activity against mouse cytomegalovirus (MCMV) in cell culture.
Conclusions:
- The CR2 region of pp150 is a viable target for peptide-based antiviral inhibitors.
- Pep-CR2 represents a promising lead compound for developing novel HCMV and MCMV therapeutics.
- Targeting the pp150-capsid interaction offers a new strategy for antiviral drug development.
