Binding Modes of Zaragozic Acid A to Human Squalene Synthase and Staphylococcal Dehydrosqualene Synthase

Abstract

Background: Fungal metabolites, zaragozic acids, are potent inhibitors against squalene synthase and S. aureus dehydrosqualene synthase. Results: Here we reported the zaragozic acid A binding mode for the head-to-head prenyltransferase drug targets. Conclusion: Zaragozic acid A presents an unexpected binding mode from the cyclopropyl-containing intermediate in both enzymes. Significance: Our structures provide a structural basis for development of potential drugs for hyperlipidemias and bacterial infection treatments.

Graphiumins, new thiodiketopiperazines from the marine-derived fungus Graphium sp. OPMF00224

“…This finding indicated that compounds inhibiting the production of staphyloxanthin could be a source of new anti-infectious agents against MRSA. On the basis of this concept, BPH-652, 7 zaragozic acid, 9 7-benzyloxyindoles 10 and flavones 11 were reported to be inhibitors of staphyloxanthin production. We started to search for such inhibitors from natural sources using our established screening system, 12 leading to the discovery of tylopilusins 13 and citridone A and its derivatives.…”

“…We started to search for such inhibitors from natural sources using our established screening system, 12 leading to the discovery of tylopilusins 13 and citridone A and its derivatives. 14 Continuing our screening program, new compounds designated graphiumins A (1) to H (8), along with two structurally related known bisdethiobis(methylthio)-deacetylaranotin (9) 15 and bisdethiobis(methylthio)-deacetylapoaranotin (10), 15 were isolated from the culture broth of the marine-derived fungus Graphium sp. OPMF00224 (Figure 1).…”

Synthesis and biological activity of Citridone A and its derivatives

“…Citridone A (1) and its 11 derivatives (7,11,14,15,16,17,19,20,21,27 and 29) were synthesized. 4 Derivatives 11, 17 and 21 (enantiomer of 1) were prepared as shown in Chart 1, according to the total synthesis of 1 we achieved previously.…”

“…1, 3 All experimental procedures for the synthesis of compounds (7,11,14,15,16,17,19,20,21,27 and 29), including citridone A (1), are summarized in Supplementary Information. (5aS,8R,8aS)-5a,7,8-Trimethyl-4-phenyl-2,5a,8,8a-tetrahydro-1H-cyclopenta [4,5] furo [3,2- (5aS,8R,8aS)-5a,8-Dimethyl-1-oxo-4-phenyl-2,5a,8,8a-tetrahydro-1H-cyclopenta [4,5] : 190.0, 164.3, 162.9, 151.8, 147.2, 134.7, 133.0, 128.5, 127.5, 127.3, 112.3, 110.8, 101.3, 56.8, 42.4, 25.1, 20 (5aS,8R,8aS)-7-(Hydroxymethyl)-5a,8-dimethyl-4-phenyl-2,5a,8,8a-tetrahydro-1H-cyclopenta [4,5]furo [3,2-c]pyridin-1-one (19). (4bS,5R,7aS)-5,6,7a-Trimethyl-3-phenyl-4b,5-dihydro-1H-cyclopenta [4,5]furo [2, 3-b]pyridin-4(7aH)-one (20). (5aR,8S,8aR)-5a,7,8-Trimethyl-4-phenyl-2,5a,8,8a-tetrahydro-1H-cyclopenta [4,5] furo [3,2- (5aS*,8aS*)-4-Phenyl-2,5a,8,8a-tetrahydro-1H-cyclopenta [4,5]furo [3,2- Assay for miconazole-potentiating activity against C. albicans using paper disks C. albicans ATCC 64548 was inoculated into a 50-ml test tube containing 10 ml seed medium (potato extract containing peptone 0.50% and glucose 1.0%), and was grown for 24 h on a rotary shaker.…”

New Approaches to Drug Discovery for Combating MRSA

“…38) This finding indicated that inhibitors of STX production could be new anti-infective drugs against MRSA. Several known compounds, BPH-652, 38) zaragozic acid, 39) 7-benzyloxyindoles 40) and flavones, 41) were reported to inhibit STX production. Among these, BPH-652, an inhibitor of squalene synthase, proved in vivo efficacy, blocking the infection of S. aureus in the host mice.…”