Linked lexitropsins and the in vitro inhibition of HIV-1 reverse transcriptase RNA-directed DNA polymerization: a novel induced-fit of 3,5 m-pyridyl bisdistamycin to enzyme-associated template-primer

Biochemistry
M E FilipowskyR E Dickerson

Abstract

Five classic DNA minor groove-binding drugs and a series of bis-linked lexitropsins based on netropsin and distamycin have been screened for their effectiveness in inhibiting transcription by HIV-1 reverse transcriptase (RT) on a poly(rA).oligo(dT) template-primer (TP). The two most effective drugs, 3,5 m-pyridyl-linked bisdistamycin (MPyr) and trans-vinyl-linked bisdistamycin (TVin), show (1) enhanced inhibition in reactions initiated with pre-incubated enzyme template-primer (ETP) and (2) reduced affinity for a "free" TP analog, when compared with the parent drug distamycin. All three drugs lack the ability to inhibit processive incorporation of nucleotide, suggesting drug intervention instead at initiation or termination of processive cycles. The two bis-linked drugs exhibit different kinetic behavior with reverse transcriptase's two substrates: template-primer and nucleotide. When primer is the variable substrate, TVin is partially noncompetitive and MPyr is dead-end competitive (Ki = 6.5 microM). With nucleotide as substrate, TVin is noncompetitive at low drug concentrations and MPyr is uncompetitive. Gel band mobility shift assays with MPyr indicate that the drug inhibits via entrapment of TP on the enzyme rather than dis...Continue Reading

References

Feb 20, 1992·Journal of Molecular Biology·K KatayanagiK Morikawa
Sep 24, 1990·European Journal of Biochemistry·O HeidenreichF Eckstein
May 1, 1986·Journal of Medicinal Chemistry·D Goodsell, R E Dickerson
Apr 20, 1986·Journal of Molecular Biology·S ArnottH S Park
Feb 1, 1988·Journal of Medicinal Chemistry·K KrowickiJ W Lown
Jun 25, 1985·Journal of Molecular Biology·M L KopkaR E Dickerson
Aug 25, 1974·Journal of Molecular Biology·V I IvanovA K Schyolkina
Jul 29, 1971·European Journal of Biochemistry·C ZimmerH Venner
Jul 1, 1980·Journal of Medicinal Chemistry·E D Clercq, O Dann
Feb 18, 1994·Journal of Molecular Biology·M D DelahuntyR L Karpel
Feb 16, 1996·Journal of Molecular Biology·R E DickersonM L Kopka

❮ Previous
Next ❯

Citations

Sep 7, 2000·Antiviral Research·Y PommierN Neamati
Jul 13, 2002·Bioorganic & Medicinal Chemistry Letters·Sanjay K SharmaJ William Lown
May 4, 2001·Journal of Biomolecular Structure & Dynamics·A N SurovayaG V Gursky
May 25, 2002·Journal of Biomolecular Structure & Dynamics·G BurckhardtC Zimmer
Dec 9, 1998·FEBS Letters·S L GrokhovskyG V Gursky
Jun 5, 2004·Bioorganic & Medicinal Chemistry Letters·Pamela K DominickMichael B Jarstfer
Jun 27, 1997·Journal of Molecular Biology·G W HanR E Dickerson
Jan 15, 2000·Journal of Biomolecular Structure & Dynamics·W H GmeinerJ W Lown
Jul 18, 2001·Journal of the American Chemical Society·A L Satz, T C Bruice
Jun 26, 2003·Journal of the American Chemical Society·Putta Mallikarjuna ReddyThomas C Bruice

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.