Chlorolissoclimides: New inhibitors of eukaryotic protein synthesis

Abstract

Lissoclimides are cytotoxic compounds produced by shell-less molluscs through chemical secretions to deter predators. Chlorinated lissoclimides were identified as the active component of am arine extract from Pleurobranchus forskalii found during ah igh-throughput screening campaign to characterize new protein synthesis inhibitors. It was demonstrated that these compounds inhibit protein synthesis in vitro, in extracts prepared from mammalian and plant cells, as well as in vivo against mammalian cells. Our results suggest that they block translation elongation by inhibiting translocation, leading to an accumulation of ribosomes on mRNA. These data provide arationale for the cytotoxic nature of this class of small molecule natural products.

Single-channel analysis of functional epithelial sodium channel (ENaC) stability at the apical membrane of A6 distal kidney cells

“…CHX and BFA are more commonly used reagents than puromycin or nocodazole, and their latency and efficacy have been well documented. CHX prevents protein synthesis following just a few minutes of exposure (31); consistent with these reports, we indeed observed effects within 5 min. The inhibitory efficiency of CHX was judged by protein translation assays that reached ϳ90% of control cells exposed to CHX for 30 min.…”

Inhibition of translation by cytotrienin A—a member of the ansamycin family

“…Ribosome-binding assays were performed essentially as described previously (Robert et al 2006). Briefly, compound was preincubated with RRL at a final KCl concentration of 150 mM for 5 min, after which 32 P-labeled CAT mRNA was included.…”

“…tRNA-binding and translocation assays were performed essentially as described (SirDeshpande and Toogood 1995;Robert et al 2006). […”

Strategies for the Design of Rna-Binding Small Molecules

“…Benzimidazole3ibis HCV IRES domain II 10 µM [158] 23 Berenil Poly(rA).2poly(rU) RNA triplex/TAR 30 µM/K d not reported [159,160] 24 Biotin Biotin aptamer 6 µM 1f27 [161] 25 Blasticidin S PTC 1kc8 [162] 26 Carbomycin 50S subunit 88% inhibition of peptide analog binding at 100 µM 1k8a [163,164] 27 Chloramphenicol 50S subunit 2 µM 1k8a [152,165] 28 Chlorolissoclimide Inhibitor of translocation 0.7 µM (IC 50 ) [166] 29 Chlorpromazine HIV-1 TAR 0.1-1 mM 1lvj (related) [148] 30 Chlortetracycline Small subunit [167] 31 Clarithromycin PTC 6.2 nM (FPA) 1j5a [156,168] 32…”

“…HIV-1 RRE <1 µM [176] 46 Delfinidin tRNA 10 µM [177] 47 Dichlorolissoclimide Inhibit eukaryotic protein synthesis 0.7 µM inhibition of protein synthesis only reported [166] 48 Doxycycline Small subunit fivefold tighter than tetracycline [167] 49 Erythromycin PTC 0.99 µM 1yi2 [178] 50 Ethidium bromide RNA/DNA heteroduplex, bulged RNA 3.3 µM [179,180] [189,190] 58 Hypoxanthine Guanine riboswitch 50 nM 2ees…”