Error-prone replication by HIV reverse transcriptase as a basis of drug design (Meeting abstract).

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

Error-prone replication by HIV reverse transcriptase as a basis of drug design (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 34:A1667 1993. Unique Identifier : AIDSLINE ICDB/93692608
Kalman TI; Jiang XJ; State Univ. of New York, Buffalo, NY 14260

Abstract: An approach was devised to target error-prone HIV replication using nucleoside analogs. A prototype analog 1-(beta-D-2-deoxyribofuranosyl)-4-acetylimidazolin-2-one (imidine, dImd), a novel ring-contracted isomer of thymidine (dThd) in which the 4-carbonyl group of thymidine (dThd) is moved out of the ring to the 5-position, was designed and synthesized. Molecular modeling studies predicted retention of base-pairing ability with a slightly distorted H-bonding geometry compared to the normal A=T base pair. This may destabilize double stranded viral DNA as well as increase misinsertion frequency. Initial tests showed modest in vitro anti-HIV activity with no cytotoxicity in 3 different host cells. The triphosphate derivative of dImd (dImdTP) inhibited HIV reverse transcriptase (RT) 500-fold stronger than DNA polymerase alpha of Molt-4 human lymphocytes. The 3'-OH of dImdTP permits elongation of viral DNA by RT. Using poly(dC)oligo(dG) template/primer system, dImdTP was more inhibitory to incorporation of 3H-dGTP by RT than was dTTP. Imidine is the first example of a nucleoside analog with an unaltered 2-deoxyribose moiety causing selective inhibition of HIV-RT.

Keywords: Animal Colonic Neoplasms/METABOLISM DNA Polymerases/METABOLISM DNA, Viral/METABOLISM Guanosine Triphosphate/METABOLISM *RNA-Directed DNA Polymerase/ANTAGONISTS & INHIB/METABOLISM Thymidine/*PHARMACOLOGY Thymine Nucleotides/METABOLISM ABSTRACT
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M9370993

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