Human cytomegalovirus (HCMV) is a pervasive and significant pathogen. At present, there is no HCMV vaccine, and the available drugs target only replication events. Thus, new therapeutic strategies are needed. HCMV fusion appears to require interactions of ␣-helical regions in viral surface glycoproteins gB and gH. Oligomers of -amino acids ("-peptides") are attractive unnatural scaffolds for mimicry of specific protein surfaces, because -peptides adopt predictable helical conformations and resist proteolysis. Here, we report the development of -peptides designed to mimic the gB heptad repeat and block HCMV entry. The most potent -peptide inhibits HCMV infection in a cell based-assay with an IC 50 of ϳ30 M. Consistent with our structure-based design strategy, inhibition is highly specific for HCMV relative to other related viruses. Mechanistic studies indicate that inhibitory -peptides act by disrupting membrane fusion. Our findings raise the possibility that -peptides may provide a general platform for development of a new class of antiviral agents and that inhibitory -peptides will constitute new tools for elucidating viral entry mechanisms.
Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion, generated from a readily prepared precursor, provides alpha-substituted-beta-amino aldehydes with 85:15 to 90:10 dr. The alpha-substituted-beta-amino aldehydes can be reduced to beta-substituted-gamma-amino alcohols, the major diastereomer of which can be isolated via crystallization or column chromatography. The amino alcohols are efficiently transformed to protected beta2-amino acids, which are valuable building blocks for beta-peptides, natural products, and other interesting molecules. Because conditions for the aminomethylation and subsequent reactions are mild, beta2-amino acid derivatives with protected functional groups in the side chain, such as beta2-homoglutamic acid, beta2-homotyrosine, and beta2-homolysine, can be prepared in this way. The synthetic route is short, and purifications are simple; therefore, this method enables the preparation of protected beta2-amino acids in useful quantities.
Previously, it was shown that cationic ␣-peptides derived from the human immunodeficiency virus TAT protein transduction domain blocked herpes simplex virus type 1 (HSV-1) entry. We now show that cationic oligomers of -amino acids ("-peptides") inhibit HSV-1 infection. Among three cationic -peptides tested, the most effective inhibition was observed for the one with a strong propensity to adopt a helical conformation in which cationic and hydrophobic residues are segregated from one another ("globally amphiphilic helix"). The antiviral effect was not cell type specific. Inhibition of virus infection by the -peptides occurred at the postattachment penetration step, with a 50% effective concentration of 3 M for the most-effective -peptide. The -peptides did not inactivate virions in solution, nor did they induce resistance to infection when cells were pretreated with the -peptides. The -peptides showed little if any toxicity toward Vero cells. These results raise the possibility that cationic -peptides may be useful antiviral agents for HSV-1 and demonstrate the potential of -peptides as novel antiviral drugs.Herpes simplex virus type 1 (HSV-1) is a significant human pathogen causing mucocutaneous lesions primarily in the oral mucosa (cold sores), as well as other sites. More-severe diseases caused by HSV-1 infection include encephalitis, meningitis, and blinding keratitis (65), and HSV-1 is the leading cause of blindness due to infection in developed countries (5). Following an initial infection, HSV-1 establishes latent infection of neurons in sensory ganglia of the host (29), from where it periodically reactivates and causes recurrent lesions at the site of primary infection. To date, none of the currently approved antivirals can eliminate an established latent infection. Because of the difficulties dealing with latency, preventing HSV-1 from entering the cell is an attractive antiviral strategy.HSV-1 entry is a complex process, involving multiple components on both the cell plasma membrane and the viral envelope. The initial interaction involves the binding of viral glycoprotein C (gC) or gB to cell surface heparan sulfate proteoglycan (58). Four viral glycoproteins, gB, gD, and the gH-gL heterodimer, are essential for the subsequent membrane fusion and entry steps (56,57). Following attachment, gD interacts with any of three cellular receptors: herpes virus entry mediator, nectin-1, and 3-O-sulfated heparan sulfate, leading to a conformational change in gD (12,13,21,22,34,39,54,62). This conformational change in gD is believed to trigger the formation of the fusion complex, which is thought to involve the sequential binding of gB to gD, followed by the binding of gH-gL to the gB-gD complex (10,20,23,24,36,41,50,62).
An enantioselective synthetic route is reported for trans-2-aminocyclopentanecarboxylic acids (ACPC) bearing geminal side chain pairs at the 4-position. Beta-peptides containing the 4,4-disubstituted ACPC residues adopt the 12-helical conformation, as demonstrated by 2D NMR analysis in aqueous solution. These 4,4-disubstituted ACPC residues display functional groups, including acidic and hydrogen bond donating groups, in a geometrically defined fashion, which should be useful for the design of beta-peptides for specific applications. [structure: see text]
Practical Synthesis of Enantiomerically Pure β 2 -Amino Acids via Proline-Catalyzed Diastereoselective Aminomethylation of Aldehydes. -A concise and versatile route for the synthesis of title compounds such as (VI) features a diastereoselective Mannich reaction to give the amino alcohols (III) as the key step. Diastereomeric ratios of the crude products in the Mannich reaction are in the range of 83:17 to 90:10 after NaBH4 treatment the major isomers are enriched via column chromatography or crystallization. The method can be used for the introduction of orthogonally protected side chains such as in (VIc) or (VId). -(CHI, Y.; ENGLISH, E. P.; POMERANTZ, W. C.; HORNE, W. S.; JOYCE, L. A.; ALEXANDER, L. R.; FLEMING, W. S.; HOPKINS, E. A.; GELLMAN*, S. H.; J. Am. Chem. Soc. 129 (2007) 18, 6050-6055; Dep. Chem., Univ. Wis., Madison, WI 53706, USA; Eng.) -Kieslich 37-181
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.