A Guide to the Russian Academy of Sciences - University of Texas ...

Studying interaction of the general transcription factors with the homological and
heterological promoter region genes. The detailed structure of the transcription
complex and the processes underlyning its formation are yet to become clear. That
is why studies of separate stages of transcription complex formation, studies of the
role of regulatory sequences and transcription factors in this formation, studies of
their affinity to the regulatory sequences to other components of the transcriptional
machinery are of importance for understanding the mechanisms of the transcription
initiation reaction and the preceding events.
Subjects of Research:
Genetical and biochemical mechanisms responsible for the drug resistance of malarial
parasite.
General Results 1993-1995:
The presence of cytochrome P-450-related genes in the plasmodial
genome and the higher amount of these genes in chloroquine(Chl)resistant
strains of parasite were demonstrated. The other finding
was that P-450-related DNA is transcribed in parasite cells and the
level of transcription is obviously elevated in the Chl-resistant strain
of parasites. This finding, along with previous biochemical data,
indicating the presence of microsomal monooxygenases(MM) in the
malarial parasite cells and its increase with augmentation of Chlresistance
(Bull.WHO 65, 381-386, 1987), confirms the linkage of
MM to resistance of Plasmodium to Chl.
Participation in State and International Programs:
RFBR
State budget financial program
Subjects of Scientific Collaboration:
Use of inhibitors of monooxygenase (MM) activities and gene related
oligodesoxynucleotides (ODN) for overcoming of chloroquine(Chl)-resistance of
malarial parasites.
The amplification of cytochrome P-450-coding genes and high level of MM-activities
may be one of the ways to provide Chl-resistance. The development of potential
inhibitors of MM may hopefully provide means for overcoming of CHl-resistance
of malarial pathogenes (Bull. WHO 65, 387-389, 1987; Antimicrob. Agents and
Chemotherapy 1993. 37:1318-1323).
At present several hypotheses have been proposed to explain the mechanism of
resistance to chloroquine ( Science. 1987. 238:1283-1285; Nature. 1990. 345:253-
255; Biochem. Pharmacol. 1992. 43:1219-1227) and we still have no unifying
argument to explain the reduced chloroquine responsiveness observed in resistant
parasite. Efforts to develop new classes of antimalarial drugs that would
circumwent drug resistance are underway. Synthetic oligonucleotides compose an
alternative class of therapeutic agents and have been demonstrated to inhibit
Plasmodium falciparum protein synthesis (NAR 1991. 19:1613-1618) and
development of P.falciparum in vitro (PNAS 1992. 89:8577-8580).
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