Prohexadione calcium is herbicidal to the sunflower root parasite Orobanche cumana.

BACKGROUND: The obligatory sunflower root parasite Orobanche cumana Wallr. deprives its host of essential nutrients, resulting in a dramatic reduction in yield and biomass. A post-emergence application with an imidazolinone herbicide on an imidazolinone-tolerant sunflower is highly effective against O. cumana. The herbicide inhibits the enzyme acetohydroxy acid synthase and consequently, growth of the parasite is inhibited, although the sunflower survives the treatment through mutations in the target enzyme. Interestingly, field studies have shown that a combined application of an imidazolinone herbicide with prohexadione resulted in reduced emergence of O. cumana compared with the sole application of the herbicide. The aim of this study was to investigate whether prohexadione is herbicidal to O. cumana. RESULTS: Prohexadione was rapidly distributed within the sunflower, reaching the roots, the site of O. cumana attack, as early as 6 h after application (HAA) on sunflower leaves. A direct impact of prohexadione on O. cumana germination was investigated and a half-maximal inhibitory concentration (IC50 ) of 84 µm prohexadione was found. In addition, the inhibition of germination by prohexadione was terminal, meaning that O. cumana seeds died after prohexadione contact as soon as they were primed for germination. Additionally, excretion studies showed that a small proportion of the applied prohexadione was excreted by sunflower roots. CONCLUSION: We show that prohexadione is an inhibitor of O. cumana germination and that the growth regulator is found in sunflower roots shortly after application. We hypothesize that prohexadione is excreted in sufficient amounts from the sunflower roots, therefore having a direct impact on O. cumana germination. © 2020 Society of Chemical Industry.

Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors.

We have used total chemical synthesis to perform high-resolution dissection of the pharmacophore of a potent anti-HIV protein, the aminooxypentane oxime of [glyoxylyl1]RANTES(2-68), known as AOP-RANTES, of which we designed and made 37 analogs. All involved incorporation of one or more rationally chosen nonnatural noncoded structures, for which we found a clear comparative advantage over coded ones. We investigated structure-activity relationships in the pharmacophore by screening the analogs for their ability to block the HIV entry process and produced a derivative, PSC-RANTES [N-nonanoyl, des-Ser1[L-thioproline2, L-cyclohexylglycine3]-RANTES(2-68)], which is 50 times more potent than AOP-RANTES. This promising group of compounds might be optimized yet further as potential prophylactic and therapeutic anti-HIV agents. The remarkable potency of our RANTES analogs probably involves the unusual mechanism of intracellular sequestration of CC-chemokine receptor 5 (CCR5), and it has been suggested that this arises from enhanced affinity for the receptor. We found that inhibitory potency and capacity to induce CCR5 down-modulation do appear to be correlated, but that unexpectedly, inhibitory potency and affinity for CCR5 do not. We believe this study represents the proof of principle for the use of a medicinal chemistry approach, above all one showing the advantage of noncoded structures, to the optimization of the pharmacological properties of a protein. Medicinal chemistry of small molecules is the foundation of modern pharmaceutical practice, and we believe we have shown that techniques have now reached the point at which the approach could also be applied to the many macromolecular drugs now in common use.

G protein-coupled receptor microarrays for drug discovery.

The dominance of G protein-coupled receptors (GPCRs) as a drug target class, coupled with the increased pace of target identification and expansion of compound libraries, presents a compelling need to develop technologies to screen multiple GPCRs simultaneously. To address this need, GPCR microarrays that require the co-immobilization of lipid molecules and the probe receptors of interest have been fabricated, using conventional robotic printing technologies. Assays to screen compounds for their pharmacological properties (binding affinity, relative potency and selectivity) using GPCR microarrays are discussed.

G protein-coupled receptor microarrays for drug discovery.

The dominance of G protein-coupled receptors (GPCRs) as a drug target class, coupled with the increased pace of target identification and expansion of compound libraries, presents a compelling need to develop technologies to screen multiple GPCRs simultaneously. To address this need, GPCR microarrays that require the co-immobilization of lipid molecules and the probe receptors of interest have been fabricated, using conventional robotic printing technologies. Assays to screen compounds for their pharmacological properties (binding affinity, relative potency and selectivity) using GPCR microarrays are discussed.