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New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2006 Aug; Vol. 50 (8), pp. 2595-601. - Publication Year :
- 2006
-
Abstract
- A series of azasterol derivatives, designed as potential inhibitors of the Delta(24)-sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the Trypanosoma brucei subsp. rhodesiense bloodstream form cultured in vitro. In order to investigate the mode of action, Trypanosoma brucei subsp. brucei 24-SMT was cloned and overexpressed and compounds were assayed for inhibitory activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.
- Subjects :
- Animals
Aza Compounds chemical synthesis
Aza Compounds chemistry
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Methyltransferases chemistry
Methyltransferases genetics
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins chemistry
Sterols chemical synthesis
Sterols chemistry
Structure-Activity Relationship
Trypanosoma brucei brucei enzymology
Trypanosoma brucei brucei growth & development
Antiprotozoal Agents pharmacology
Aza Compounds pharmacology
Enzyme Inhibitors pharmacology
Methyltransferases antagonists & inhibitors
Sterols pharmacology
Trypanocidal Agents pharmacology
Trypanosoma brucei brucei drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0066-4804
- Volume :
- 50
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 16870747
- Full Text :
- https://doi.org/10.1128/AAC.01508-05