Butyl DNJ is a drug artificially derived from plant sugars. In the test-tube it disrupts the normal formation of the complex sugars which make up HIV's outer (envelope) protein called gp120. This prevents the virus from binding onto the CD4 molecule on human cells and infecting them.

Butyl DNJ stands for N-butyl deoxynojirimycin. The drug is sometimes referred to as deoxynojirimycin, BuDNJ or by the codename SC-48334. It is manufactured by the drug company G D Searle & Co.

Current use

Butyl DNJ is an unlicensed, experimental drug. Clinical trials have found no clear evidence that it is effective, and the company is not expected to pursue its development. Reported side-effects are mainly gastro-intestinal such as cramping, bloating and diarrhoea. These side-effects seem to be less common in people with early ARC than in people with more advanced disease. In animals butyl DNJ also caused liver problems, decreased platelet counts and eye cataracts, but none of these have yet been observed in humans.

Current developments

Researchers have developed a pro-drug of butyl-DNJ, i.e. a substance that is broken down into butyl-DNJ within the body. This pro-drug, known by the codename SC-49483, seems to cause fewer gastro-intestinal side-effects.

Key research

In vitro, butyl-DNJ inhibits protein N-glycosylation, which Montefiori reports as being essential to the ability of HIV to infect healthy cells. Glycosylation inhibitors prevent post-translational changes in gp120 and hence inhibit viral binding. Karpas reported that butyl-DNJ was the most effective amino sugar inhibitor of HIV in in vitro tests. Gruters has reported decreased infectivity of HIV as well as inhibition of cell fusion in the presence of butyl-DNJ.

Ratner reported that in vitro the combination of butyl-DNJ plus ddI, ddC or AZT reduced reverse transcriptase activity more than any single agent and the effects on the number of infectious virus particles were additive or synergistic.

Tierney conducted a phase I tolerability and pharmacokinetics study of Butyl-DNJ among people with advanced HIV disease. The major toxicity was diarrhoea.

Fischl enrolled 118 people with CD4 counts between 200-500 and less than 12 weeks prior AZT therapy in a phase II double-blind randomized study comparing AZT monotherapy with the combination of AZT plus Butyl-DNJ (1000 mg every 8 hours) for 24 weeks. No significant difference in change in CD4 count or virological markers between the two groups was observed. However, there was a trend for combination recipients to experience a greater decline in detectable levels of serum p24 antigen. In participants with prior AZT experience, those receiving the combination had CD4 count increases during the first 8 weeks of treatment, compared with declines in CD4 count among AZT monotherapy recipients.

Smith reported that SC-49483, a pro-drug of Butyl-DNJ, was significantly less likely to cause loose or watery stool than Butyl-DNJ itself.

References

Fischl MA et al. The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm³. JAIDS 7(2):139-147, 1994.

Gruters RA et al. Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidases. Nature 330(5):74-77, 1987.

Karpas A et al. Antiviral effects of amino sugars: potency of N-butyl deoxynojirimycin (Bu-DNJ). 5th Intl Conf AIDS, Montreal, abstract MCO 18, 1989.

Montefiori DC et al. Role of protein N-glycosylation in pathogenesis of human immunodeficiency virus type 1. PNAS 85:9248-9252, 1988.

Ratner L et al. Mechanism of action of N-butyl deoxynojirimycin in inhibiting HIV -1 infection and activity in combination with nucleoside analogs. AIDS Res Hum Retroviruses 9(4):291-297, 1993.

Smith S et al. Multiple oral dose safety and pharmacokinetics of SC-49843 (N-butyl deoxynojirimycin [NB-DNJ] prodrug). 1st Natl Conf on Human Retroviruses, Washington, abstract 573, 1993.

Tierney M et al. The tolerability and pharmacokinetics of N butyl deoxynojirimycin in patients with advanced HIV disease (ACTG 100). 33rd ICAAC, New Orleans, abstract 46, 1993.