Jason M. Cox

Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155

ABSTRACT BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the “phenylalanine 43 cavity” and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.

C-Glycosides to fused polycyclic ethers

This manuscript describes the synthesis of fused polycyclic ethers from the coupling of C-glycoside forming reactions with ring closing metathesis and acid mediated annulation reactions.

Enol ether–olefin ring closing metathesis using the Grubbs ruthenium imidazole catalyst

Abstract This letter reports our successful use of the Grubbs ruthenium imidazole alkylidene catalyst in enol ether–olefin ring closing metathesis reactions.

Total synthesis of (-)-2-epi-peloruside A.

A convergent synthesis of (-)-2-epi-peloruside A has been achieved. Highlights include implementation of multicomponent type I anion relay chemistry (ARC) to unite 2-TBS-1,3-dithiane with two epoxides to construct the eastern hemisphere, a late-stage dithiane union to secure the complete, fully functionalized carbon backbone, and Yamaguchi macrolactonization, which led to (-)-2-epi-peloruside A via an unexpected epimerization at C(2).