PMID- 20194690
OWN - NLM
STAT- MEDLINE
DCOM- 20100722
LR  - 20211020
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 54
IP  - 5
DP  - 2010 May
TI  - Evaluation of nucleoside hydrolase inhibitors for treatment of African 
      trypanosomiasis.
PG  - 1900-8
LID - 10.1128/AAC.01787-09 [doi]
AB  - In this paper, we present the biochemical and biological evaluation of 
      N-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic 
      agents against trypanosomiasis. Previously, a library of 52 compounds was 
      designed and synthesized as potent and selective inhibitors of Trypanosoma vivax 
      inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the 
      compounds were tested against bloodstream-form Trypanosoma brucei brucei, only 
      one inhibitor, N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol 
      (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration 
      [IC(50)] +/- standard error, 0.49 +/- 0.31 microM). Validation in an in vivo 
      model of African trypanosomiasis showed promising results for this compound. 
      Several experiments were performed to investigate why only UAMC-00363 showed 
      antiparasitic activity. First, the compound library was screened against T. b. 
      brucei IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the 
      previously demonstrated inhibitory effects of the compounds on T. vivax IAG-NH. 
      Second, to verify the uptake of these compounds by T. b. brucei, their affinities 
      for the nucleoside P1 and nucleoside/nucleobase P2 transporters of T. b. brucei 
      were tested. Only UAMC-00363 displayed significant affinity for the P2 
      transporter. It was also shown that UAMC-00363 is concentrated in the cell via at 
      least one additional transporter, since P2 knockout mutants of T. b. brucei 
      displayed no resistance to the compound. Consequently, no cross-resistance to the 
      diamidine or the melaminophenyl arsenical classes of trypanocides is expected. 
      Third, three enzymes of the purine salvage pathway of procyclic T. b. brucei 
      (IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated 
      using RNA interference. The findings from all these studies showed that it is 
      probably not sufficient to target only the nucleoside hydrolase activity to block 
      the purine salvage pathway of T. b. brucei and that, therefore, it is possible 
      that UAMC-00363 acts on an additional target.
FAU - Berg, Maya
AU  - Berg M
AD  - Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
FAU - Kohl, Linda
AU  - Kohl L
FAU - Van der Veken, Pieter
AU  - Van der Veken P
FAU - Joossens, Jurgen
AU  - Joossens J
FAU - Al-Salabi, Mohammed I
AU  - Al-Salabi MI
FAU - Castagna, Valeria
AU  - Castagna V
FAU - Giannese, Francesca
AU  - Giannese F
FAU - Cos, Paul
AU  - Cos P
FAU - Versees, Wim
AU  - Versees W
FAU - Steyaert, Jan
AU  - Steyaert J
FAU - Grellier, Philippe
AU  - Grellier P
FAU - Haemers, Achiel
AU  - Haemers A
FAU - Degano, Massimo
AU  - Degano M
FAU - Maes, Louis
AU  - Maes L
FAU - de Koning, Harry P
AU  - de Koning HP
FAU - Augustyns, Koen
AU  - Augustyns K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100301
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antiprotozoal Agents)
RN  - 0 (Carrier Proteins)
RN  - 0 (N-(9-deazaadenin-9-yl)methyl-1,4-dideoxy-1,4-iminoribitol)
RN  - 0 (RNA, Small Interfering)
RN  - 673LC5J4LQ (Pentamidine)
RN  - EC 3.2.2.- (N-Glycosyl Hydrolases)
RN  - K72T3FS567 (Adenosine)
RN  - ZF3786Q2E8 (Melarsoprol)
SB  - IM
MH  - Adenosine/*analogs & derivatives/chemistry/pharmacokinetics
MH  - Animals
MH  - Antiprotozoal Agents/chemistry/*pharmacokinetics
MH  - Carrier Proteins/metabolism
MH  - Gene Knockdown Techniques
MH  - Melarsoprol/chemistry
MH  - Mice
MH  - Models, Chemical
MH  - N-Glycosyl Hydrolases/*antagonists & inhibitors/genetics
MH  - Pentamidine/chemistry
MH  - RNA, Small Interfering
MH  - Trypanosoma brucei brucei/*drug effects/enzymology/genetics
MH  - Trypanosomiasis, African/*drug therapy/metabolism
PMC - PMC2863631
EDAT- 2010/03/03 06:00
MHDA- 2010/07/23 06:00
PMCR- 2010/11/01
CRDT- 2010/03/03 06:00
PHST- 2010/03/03 06:00 [entrez]
PHST- 2010/03/03 06:00 [pubmed]
PHST- 2010/07/23 06:00 [medline]
PHST- 2010/11/01 00:00 [pmc-release]
AID - AAC.01787-09 [pii]
AID - 1787-09 [pii]
AID - 10.1128/AAC.01787-09 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2010 May;54(5):1900-8. doi: 10.1128/AAC.01787-09. 
      Epub 2010 Mar 1.