Novel Synthetic Polyamines Are Effective in the Treatment of Experimental Microsporidiosis, an Opportunistic AIDS-Associated Infection

Abstract

Microsporidia are eukaryotic obligate intracellular protists that are emerging pathogens in immunocompromised hosts, such as patients with AIDS or patients who have undergone organ transplantation. We have demonstrated in vitro and in vivo that synthetic polyamine analogs are effective antimicrosporidial agents with a broad therapeutic window. CD8-knockout mice or nude mice infected with the microsporidian Encephalitozoon cuniculi were cured when they were treated with four different novel polyamine analogs at doses ranging from 1.25 to 5 mg/kg of body weight/day for a total of 10 days. Cured animals demonstrated no evidence of parasitemia by either PCR or histologic staining of tissues 30 days after untreated control animals died.

Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells

“…N 1 , N 11 -bis(ethyl)norspermine (BENSpm), N 1 -ethyl-N 11 -(cycloheptyl)methyl-4,8,diazaundecane (CHENSpm), CGC-11144 and CGC-11172 (previously named SL-11144 and SL-11172) were synthesized as previously reported. 11,13,20 Stock solutions (10 mM in ddH 2 O) of each analogue were diluted with medium to the desired concentrations for specific experiments. The human breast cancer MCF-7 cells were maintained in DMEM supplemented with 5% fetal bovine serum, 2 mM glutamine and incubated at 37˚C in a 5% CO 2 atmosphere.…”

“…10 Recently, a series of new polyamine analogues designated conformationally restricted, cyclic and oligoamine analogues have been developed. [11][12][13] Some of these agents incorporate alterations that limit the free rotation of the single bonds in otherwise flexible molecules such as spermine or its analogues, thus restricting the molecular conformation that they may assume. Oligoamine analogues consist of synthetic octa-, deca-, dodeca-and tetradecamines with longer chains than natural mammalian polyamine molecules, with or without conformational restriction.…”

Probing tRNA interaction with biogenic polyamines

“…However, it seems that a large fraction of polyamines exists in polyamine-RNA adducts, and the major part of their cellular function may be explained through structural changes of RNA by polyamines (Watanabe et al 1991;Cohen 1998;Igarashi and Kashiwagi 2000). On the other hand, the potential effectiveness of polyamine analogs, as antiproliferative agents against many tumor cell lines and infectious diseases, provides evidence for nucleic acid interaction with the biogenic polyamines (Li et al 1996;Frydman and Valasinas 1999;Fernandez et al 2000;Bacchi et al 2002;Thomas et al 2002;Frydman et al 2003;Thomas and Thomas 2003).…”

Polyamine Analogues Bind Human Serum Albumin

“…5,14 New synthetic polyamines were also found to be effective against AIDS-associated infection. 15 Interactions of biogenic polyamine and polyamine analogues with DNA and RNA are extensively investigated. [16][17][18] Complexation of biogenic polyamines, e.g., spermine, spermidine and putrescine with human serum albumin has been studied and the effect of polyamine-HSA complexation on protein secondary structure was recently reported.…”

“…Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues such as 1,3,7,11,7,11,15, in aqueous solution at physiological conditions, using a constant protein concentration and various polyamine contents (μM to mM). FTIR, UVvisible and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure.…”