Berkeleyones and related meroterpenes from a deep water acid mine waste fungus that inhibit the production of interleukin 1-β from induced inflammasomes

Abstract

The Berkeley Pit, an acid mine waste lake, is a source of extremophilic microorganisms that produce interesting bioactive compounds. We have previously reported the isolation of berkeleydione (1), berkeleytrione (2), the berkeleyacetals, and the berkeleyamides from the Pit Lake fungus Penicillium rubrum. In this paper we report the isolation and characterization of berkeleyones A-C (4, 5, and 7) as well as previously described preaustinoid A (3) and A1(6) from this same fungus. These compounds were evaluated as inhibitors of the signaling enzyme caspase-1 and as potential inhibitors of interleukin 1-β production by inflammasomes in induced THP-1 cell line assays.

Fig 1

Docking of berkeleydione 1 (orange, up conformation in A, pink, down conformation in B), preaustinoid A 3 (purple, A), berkeleyone B 2 (green, B) into 1RWV, showing the top scoring pose across the discussed ensemble of caspase-1 structures. Atoms in the protein are colored according to atom type (oxygen, red; nitrogen, blue; sulfur, yellow), with polar hydrogens colored cyan. Arg383, which bisects the active site groove, is indicated. The catalytic pocket can be seen behind the ligands in A.