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1.
ACS Med Chem Lett ; 12(12): 1955-1961, 2021 Dec 09.
Article in English | MEDLINE | ID: mdl-34917260

ABSTRACT

Viral proteases have been established as drug targets in several viral diseases including human immunodeficiency virus and hepatitis C virus infections due to the essential role of these enzymes in virus replication. In contrast, no antiviral therapy is available to date against flaviviral infections including those by Zika virus (ZIKV), West Nile virus (WNV), or dengue virus (DENV). Numerous potent inhibitors of flaviviral proteases have been reported; however, a huge gap remains between the in vitro and intracellular activities, possibly due to low cellular uptake of the charged compounds. Here, we present an alternative, nanoparticular approach to antivirals. Conjugation of peptidomimetic inhibitors and cell-penetrating peptides to dextran yielded chemically defined nanoparticles that were potent inhibitors of flaviviral proteases. Peptide-dextran conjugates inhibited viral replication and infection in cells at nontoxic, low micromolar or even nanomolar concentrations. Thus, nanoparticular antivirals might be alternative starting points for the development of broad-spectrum antiflaviviral drugs.

2.
Org Lett ; 22(8): 2976-2980, 2020 04 17.
Article in English | MEDLINE | ID: mdl-32223201

ABSTRACT

The flexible variation of peptidomimetics is of great interest for the identification of optimized protein ligands. Here we present a general concept for introducing side-chain modifications into peptides using triarylphosphonium amino acids. Building blocks 4a and 4b are activated for amidation and incorporated into stable peptides. The obtained phosphoranylidene peptides undergo Wittig olefinations and 1,3-dipolar cycloaddition reactions, yielding peptidomimetics with vinyl ketones and 5-substituted 1,2,3-triazoles as non-native peptide side chains.


Subject(s)
Aldehydes/chemistry , Amino Acids/chemistry , Peptides/chemistry , Peptidomimetics/chemical synthesis , Phosphoranes/chemistry , Cycloaddition Reaction , Molecular Conformation , Peptidomimetics/chemistry
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