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.
Highlights
Human Cytomegalovirus (HCMV), a betaherpesvirus, infects the majority of the world’s population but acute disease is manifested only in a small proportion of infected individuals [1]
Pep-conserved region 2 (CR2)-treated infected cells showed significantly smaller plaque sizes compared to the mock-treated group, indicating reduction in virus spread to the adjacent cells in a foci, inhibiting virus growth (Figure 3B,C)
Samples were analyzed with one-way ANOVA in GraphPad Prism 9.0 and thisanalyzed study, we utilized multiple toPrism demonstrate that CR2 of CMV teg cells from virus-induced lytic cell death
Summary
Human Cytomegalovirus (HCMV), a betaherpesvirus, infects the majority of the world’s population but acute disease is manifested only in a small proportion of infected individuals [1]. Primary infection or reactivation of latent virus can cause life-threatening complications in immunocompromised individuals such as AIDS patients and transplant recipients. Primary maturation begins in the host-cell nucleus where viral genome replication, capsid assembly and encapsidation take place [5]. The nucleocapsids (NC) migrate from the nucleus to the cytoplasm During this nuclear egress, the nucleocapsid first undergoes a primary envelopment at the inner nuclear membrane, traverses through the nuclear envelope, followed by de-envelopment at the outer nuclear membrane, and reaches the cytoplasm where it accumulates within a ring-shaped perinuclear structure known as the cytoplasmic virus assembly compartment (vAC) where the secondary or final steps of virion maturation occur [4,5,6,7,8,9]
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