Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.

To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.

[Screening and taxonomic identification of endophytic fungi with antitumor and antioxidant activities from Artemisia lactiflora].

Artemisia lactiflora is an important medicinal plant in China. The antitumor and antioxidant activities of the extracts of 54 endophytic fungi from the plant were screened via MTT assay and DPPH scavenging radical assay, respectively. The bioactive strains were identified based on similarity of 5.8S gene and internal transcribed spacer (ITS) sequences. The results showed that extracts from ten (18.5%) isolates exhibited antitumor activity, and which from two (3.7%) isolates exhibited antioxidant activity. The Alternaria sp. GYBH47 strain was simultaneously having antagonistic activity against HL-60 leukemia, MCF-7 breast and COLO205 colon cell lines, and Phomopsis sp. GYBH42 strain having cytotoxic and antioxidant activities. The results indicated that endophytic fungi from Artemisia lactiflora are potential resources to find valuable bioactive components.

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors.

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.