Diene incorporation by a dehydratase domain variant in modular polyketide synthases.

Modular polyketide synthases (PKSs) are biosynthetic assembly lines that construct structurally diverse natural products with wide-ranging applications in medicine and agriculture. Various mechanisms contribute to structural diversification during PKS-mediated chain assembly, including dehydratase (DH) domain-mediated elimination of water from R and S-configured 3-hydroxy-thioesters to introduce E- and Z-configured carbon-carbon double bonds, respectively. Here we report the discovery of a DH domain variant that catalyzes the sequential elimination of two molecules of water from a (3R, 5S)-3,5-dihydroxy thioester during polyketide chain assembly, introducing a conjugated E,Z-diene into various modular PKS products.

Identification of nonstandard macrocyclic peptide ligands through display screening.

Techniques facilitating the synthesis and screening of very high diversity nonstandard macrocyclic peptide libraries have led to such compounds receiving increasing attention as potential drug candidates. Specifically, approaches which allow the use of non-proteinogenic amino acids are proving to be particularly effective, since they expand the accessible chemical space of the starting library and thus allow the identification of compounds with structural similarity to known drugs. This review focuses on mRNA display screening platforms for drug discovery and their combined use with genetic code reprogramming to identify novel macrocyclic peptides with high affinities for disease-related targets of interest.

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode.

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.

Azapropellanes with anti-influenza a virus activity.

The synthesis of several [4,4,3], [4,3,3], and [3,3,3]azapropellanes is reported. Several of the novel amines displayed low-micromolar activities against an amantadine-resistant H1N1 strain, but they did not show activity against an amantadine-sensitive H3N2 strain. None of the tested compounds inhibit the influenza A/M2 proton channel function.

Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine.

Dimerization of pyramidalized 3,4,8,9-tetramethyltetracyclo [4.4.0.0(3,9).0(4,8)]dec-1(6)-ene to a hydrocarbon featuring four cyclohexane rings in boat conformations.

The synthesis, chemical trapping, and dimerization of a highly pyramidalized alkene is reported. Its dimer is a unique nonacycle featuring three planar cyclobutane rings, four cyclopentane rings, and four cyclohexane rings in boat conformations. The X-ray diffraction analysis showed a H-H distance between the flagpole hydrogen atoms of 1.

3-Azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant.

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors.

The synthesis of phenylene-ethynylene rods and their use as rigid spacers is described. Alternation of a Sonogashira reaction and silyl group cleavage was used to obtain rigid spacers with even and odd numbers of phenylene units. Preliminary applications of these rods in divalent systems are shown.