Identification of an Optimized Clinical Development Candidate from Cilagicin, an Antibiotic That Evades Resistance by Dual Polyprenyl Phosphate Binding.

Cilagicin is a dual polyprenyl phosphate binding lipodepsipeptide antibiotic with strong activity against clinically relevant Gram-positive pathogens while evading antibiotic resistance. Cilagicin showed high serum binding that reduced its in vivo efficacy. Cilagicin-BP, which contains a biphenyl moiety in place of the N-terminal myristic acid found on cilagicin, showed reduced serum binding and increased in vivo efficacy but decreased potency against some pathogens.

Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics.

DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products.

DPP8/9 are not Required to Cleave Most Proline-Containing Peptides.

Small molecule inhibitors of the intracellular serine peptidases DPP8 and DPP9 (DPP8/9) activate the NLRP1 and CARD8 inflammasomes, but the key DPP8/9 substrates have not yet been identified. DPP8/9 cleave after proline to remove N-terminal dipeptides from peptides or proteins, and studies using pseudo-peptide reporter substrates have suggested that these enzymes may play key roles in the catabolism of many proline-containing peptides generated by the proteasome. Here, we evaluated the degradation of a wide array of actual peptides in cell lysates, and discovered that DPP8/9 are not in fact involved in the processing of the vast majority of proline-containing peptides.

Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation.

Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome.

Protein folding stress potentiates NLRP1 and CARD8 inflammasome activation.

NLRP1 and CARD8 are related pattern-recognition receptors (PRRs) that detect intracellular danger signals and form inflammasomes. Both undergo autoproteolysis, generating N-terminal (NT) and C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the stimuli that trigger NT degradation have not been fully elucidated.

M24B aminopeptidase inhibitors selectively activate the CARD8 inflammasome.

Inflammasomes are multiprotein complexes that sense intracellular danger signals and induce pyroptosis. CARD8 and NLRP1 are related inflammasomes that are repressed by the enzymatic activities and protein structures of the dipeptidyl peptidases 8 and 9 (DPP8/9). Potent DPP8/9 inhibitors such as Val-boroPro (VbP) activate both NLRP1 and CARD8, but chemical probes that selectively activate only one have not been identified.

DPP9's Enzymatic Activity and Not Its Binding to CARD8 Inhibits Inflammasome Activation.

Inflammasomes are multiprotein complexes formed in response to pathogens. NLRP1 and CARD8 are related proteins that form inflammasomes, but the pathogen-associated signal(s) and the molecular mechanisms controlling their activation have not been established. Inhibitors of the serine dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both NLRP1 and CARD8.

2-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors of Cystathionine γ-Lyase (CSE).

Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role.

Oxamidation of Unsaturated O-Alkyl Hydroxamates: Synthesis of the Madangamine Diazatricylic (ABC Rings) Skeleton.

A novel approach to the diazatricyclic madangamine ABC ring system and the synthesis of an advanced, differentially protected intermediate for the synthesis of madangamine D is reported. Central to the success of this approach is the iodine(III)-mediated intramolecular oxamidation of an unsaturated O-methyl hydroxamate, a π-N-type cyclization which proceeds in high yield and with complete regioselectivity to generate the 2-azabicyclo[3.3.