Short cationic peptides derived from DNA-binding proteins, of which HIV Tat is a prototype, can cross the membranes of living cells, and they can bring covalently attached moieties (proteins, drugs) along with them. We show that a beta-amino acid analogue of Tat 47-57 enters HeLa cells with comparable efficiency to Tat 47-57 itself (YGRKKRRQRRR). The beta-peptide is comprised of residues that bear the appropriate side chain at the beta-carbon. Both the alpha- and the beta-peptide were conjugated to fluorescein at the N terminus, and cell penetration was monitored by confocal fluorescence microscopy. Deletion of the three C-terminal arginine residues from the alpha-peptide abolished translocation activity, consistent with prior reports, and deletion of the three C-terminal beta3-homoarginine residues from the beta-peptide had a similarly adverse effect. Thus, alpha- and beta-peptide translocation processes show similar length/charge dependence. The beta-peptide appeared to be largely unfolded in water, which is consistent with the behavior of short Tat-derived alpha-peptides, but in methanol the beta-peptide adopted a helical conformation, in contrast to short Tat-derived alpha-peptides. Our results show that neither altering the oligomeric backbone (amide group spacing) nor increasing the intrinsic propensity to adopt a specific secondary structure affects translocation activity.
[structure: see text] Poly(1) kills bacteria (Gram-positive and -negative) and lyses human erythrocytes; this biocidal profile is similar to that of the peptide toxin mellitin. Poly(1) has antibacterial activity comparable to that of a potent derivative of the host defense peptide magainin II, but lacks magainin's selectivity for bacteria over erythrocytes. An analogous N-quaternized polymer, poly(3), is less biocidal than poly(1), suggesting that reversible N-protonation leads to greater biocidal activity than does irreversible N-quaternization.
[structure: see text] The interaction between the HIV-1 Tat protein and the TAR RNA element in the nascent viral genomic transcript is required for viral replication. An 11-residue beta-peptide (1), an all-beta homologue of the Arg-rich region Tat 47-57, binds TAR RNA with K(d) = 29 +/- 4 nM. A control beta-peptide (2) in which all Arg side chains are replaced by Lys side chains shows increased affinity but decreased specificity for wild-type vs bulge-deleted TAR RNA, as do the alpha-peptide analogues of 1 and 2.
Therapy for hepatitis C virus (HCV) infection is on the cusp of a new era. Until now, standard of care (SOC) therapy has involved interferon (IFN) and ribavirin. With the first successful phase 3 trials of specific targeted antiviral therapy for HCV (STAT-C) compounds, as well as three trials in progress giving the first glimpse of IFN-free combinations of STAT-C agents, this review looks ahead to the new classes of anti-HCV agents currently in clinical development. Successful pharmacologic control of HIV and TB frames the discussion, as well as consideration of the mutation frequency of HCV replication. Maximizing synergy between agents and minimizing cumulative toxicity will be critical to the design of future IFN-free STAT-C regimens.
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