No abstract

The replication of human cytomegalovirus (HCMV) involves a process termed nuclear egress, which enables translocation of newly formed viral capsids from the nucleus into the cytoplasm. The HCMV core nuclear egress complex (core NEC), a heterodimer of viral proteins pUL50 and pUL53, is therefore considered a promising target for new antiviral drugs. We have recently shown that a 29-mer peptide presenting an N-terminal alpha-helical hook-like segment of pUL53, through which pUL53 interacts with pUL50, binds to pUL50 with high affinity, and inhibits the pUL50–pUL53 interaction in vitro. Here, we show that this peptide is also able to interfere with HCMV infection of cells, as well as with core NEC formation in HCMV-infected cells. As the target of the peptide, i.e., the pUL50–pUL53 interaction, is localized at the inner nuclear membrane of the cell, the peptide had to be equipped with translocation moieties that facilitate peptide uptake into the cell and the nucleus, respectively. For the resulting fusion peptide (NLS-CPP-Hook), specific cellular and nuclear uptake into HFF cells, as well as inhibition of infection with HCMV, could be demonstrated, further substantiating the HCMV core NEC as a potential antiviral target.

Three chiral tridentate N^N^S coordinating pyridine‐carbaldehyde (S)‐N4‐(α‐methylbenzyl)thiosemicarbazones (HTSCmB) were synthesised along with lysine‐modified derivatives. One of them was selected and covalently conjugated to the cell‐penetrating peptide sC18 by solid‐phase peptide synthesis. The HTSCmB model ligands, the HTSCLp derivatives and the peptide conjugate rapidly and quantitatively form very stable PtII chlorido complexes [Pt(TSC)Cl] when treated with K2PtCl4 in solution. The Pt(CN) derivatives were obtained from one TSCmB model complex and the peptide conjugate complex through Cl−→CN− exchange. Ligands and complexes were characterised by NMR, IR spectroscopy, HR‐ESI‐MS and single‐crystal XRD. Intriguingly, no decrease in cell viability was observed when testing the biological activity of the lysine‐tagged HdpyTSCLp, its sC18 conjugate HdpyTSCL‐sC18 or the PtCl and Pt(CN) conjugate complexes in three different cell lines. Thus, given the facile and effective preparation of such Pt‐TSC‐peptide conjugates, these systems might pave the way for future use in late‐stage labelling with Pt radionuclides and application in nuclear medicine.

No abstract

Cell-penetrating peptides (CPPs) have emerged as versatile tools to increase the intracellular accumulation of different kinds of cargoes. For an efficient cellular uptake and drug delivery, their organization into a distinct and stable secondary structure at the outer surface of the plasma membrane is a hallmark and supports optimal lipid–peptide interactions. Incorporation of hydrophobic moieties, such as carboranes (CBs), has the potential to increase the lipophilicity of peptides, and thus, to facilitate the formation of secondary structures. Herein, we present synthesis and biophysical as well as biological characterization of carborane-CPP conjugates having incorporated one or more CB clusters. Our results highlight the possibility to modulate the secondary structure of CPPs by the addition of CB’s leading to constructs with altered membrane activity and promising use in terms of nucleic acid delivery.