Joseph A. Martin

Inhibitors of HIV proteinase

This article briefly describes the identification of HIV proteinase as a potential target for antiviral chemotherapy, and discusses some of the strategies which have been used to discover inhibitors of this essential viral enzyme. Preclinical efficacy data are presented for selected inhibitors, and the ability of such compounds to generate a virus with reduced sensitivity is compared to that of reverse transcriptase inhibitors. The possibility of clinically useful synergistic interactions between inhibitors of HIV proteinase and other antiviral agents is also considered.

The inhibitory activity of a peptide derivative against the growth of simian immunodeficiency virus in C8166 cells

The peptide derivative Ro 31-8959 is a potent and selective inhibitor of the aspartic proteinases encoded by HIV-1 and HIV-2 and it arrests the growth of both viruses in cell culture. We have demonstrated similar effects against the simian immunodeficiency virus SIVmac251 in the human T-cell line, C8166 (ED50 = 6nM) with a therapeutic index of 4,500. The antiviral activity of Ro 31-8959 was 250 and 22 times greater than that of ddI and ddC, respectively. The mode of action was confirmed by accumulation of the polyprotein p55 with concomitant reduction of the cleavage product, p27, and by the production of immature virions.

Nucleoside Analogues as Highly Potent and Selective Inhibitors of Herpes Simplex Virus Thymidine Kinase

A series of carboxamide derivatives of 5-amino-2,5-dideoxy-5-ethyluridine has been prepared as inhibitors of HSV-TK (herpes simplex virus thymidine kinase). The most potent compounds were derived from xanthene, thioxanthene and dihydroanthracene carboxylic acids. The lead compounds show subnanomolar IC(50) values against HSV TKs.

An unusual reaction of myo-inositol with sulphur tetrafluoride

Abstract Myo-inositol was treated with a mixture of sulphur tetrafluoride and anhydrous hydrofluoric acid to yield a novel compound, the cyclic sulphite ester of 2β,3β-difluoro-7-oxabicyclo[2,2,1]heptane- 5α,6α-diol. The structural assignment and possible mechanism is described.

Fluorination of (+)-chiro-inositol with SF4/HF to give 2α,3β-difluoro-7-oxabicyclo[2.2.1]heptane-5α,6α-sulfite

Abstract The fluorination of (+)- chiro -inositol with SF 4 /HF under moderate conditions affords a single product studied by 1 H and 19 F and 13 C NMR spectroscopy. These have been fully assigned with the aid of other physical techniques and compared with a computer-generated model. This data indicate the product to be 2α,3β-difluoro-7-oxabicyclo[2.2.1]heptane-5α,6α-sulfite 3 which was subsequently confirmed by single-crystal X-ray analysis. A mechanism for the reaction is proposed and is compared with that proposed for the formation of the product obtained from the fluorination of myo -inositol.

Carbocyclic analogues of hydroxyethylamine containing inhibitors of HIV proteinase

Abstract The cyclohexane analogues 3 and 4 of the piperidine carboxamide 1 have been synthesized. The trans isomer 3 is more potent than the hydroxyethylamine 1 versus HIV-1 proteinase, while the cis isomer 4 is less potent.