Jacques Banville

Changes to the HIV Long Terminal Repeat and to HIV Integrase Differentially Impact HIV Integrase Assembly, Activity, and the Binding of Strand Transfer Inhibitors

Human immunodeficiency virus (HIV) integrase enzyme is required for the integration of viral DNA into the host cell chromosome. Integrase complex assembly and subsequent strand transfer catalysis are mediated by specific interactions between integrase and bases at the end of the viral long terminal repeat (LTR). The strand transfer reaction can be blocked by the action of small molecule inhibitors, thought to bind in the vicinity of the viral LTR termini. This study examines the contributions of the terminal four bases of the nonprocessed strand (G2T1C–1A–2) of the HIV LTR on complex assembly, specific strand transfer activity, and inhibitor binding. Base substitutions and abasic replacements at the LTR terminus provided a means to probe the importance of each nucleotide on the different functions. An approach is described wherein the specific strand transfer activity for each integrase/LTR variant is derived by normalizing strand transfer activity to the concentration of active sites. The key findings of this study are as follows. 1) The G2:C2 base pair is necessary for efficient assembly of the complex and for maintenance of an active site architecture, which has high affinity for strand transfer inhibitors. 2) Inhibitor-resistant enzymes exhibit greatly increased sensitivity to LTR changes. 3) The strand transfer and inhibitor binding defects of a Q148R mutant are due to a decreased affinity of the complex for magnesium. 4) Gln148 interacts with G2, T1, and C–1 at the 5′ end of the viral LTR, with these four determinants playing important and overlapping roles in assembly, strand transfer catalysis and high affinity inhibitor binding.

Asymmetric synthesis of aldehydes via alkylation of lithiated chiral α-phenethylimines

Abstract The lithiation and alkylation of three aldehydes in the form of their α-phenethylimines has been shown to yield chiral α-alkylaldehydes of 67–70% optical purity.

Solid phase synthesis of novel pyrrolidinedione analogs as potent HIV-1 integrase inhibitors.

A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at R(1), R(2), and R(3) of the pyrrolidinedione scaffold. The resulting library samples were assayed for HIV-1 integrase activity and analyzed to determine the R(1), R(2), and R(3) reagent contributions towards the activity.

Reinvestigation of the regioselectivity of deprotonation of ketone dimethylhydrazones

Abstract The lack of regioselectivity in the deprotonation of ketone dimethylhydrazones by lithium diethylamide has been determined by 13 C NMR spectroscopy of deuterium labelled samples.

REINVESTIGATION OF THE REGIOSELECTIVITY OF DEPROTONATION OF KETONE DIMETHYLHYDRAZONES

Methyl-ethyl-keton-dimethylhydrazon (I) wird nach Umwandlung in das Anion mit Trideuteromethyliodid (II) zu (III) methyliert und dann weiter zu (V) und (VI) mit Methyliodid (IV) methyliert.

Quantitative measurement of syn stabilization of lithiated aldimines

The lithiation and alkylation of aliphatic aldimines has been shown to give syn and anti products in a ratio of 96:4 which is interpreted as representing a minimum value for the syn to anti ratio of the lithiated aldimine intermediates; the factor responsible for the preferential syn stabilization, though not yet identified, is determined to have a magnitude of at least 18 kJ mol–1.