AIDSWEEKLY Plus, Monday, 5 May 1997
Daniel J. DeNoon, Senior Editor
Structural analysis of delavirdine may lead to improvements in this and other anti-HIV drugs.
Delavirdine is a member of the broad class of drugs known as non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs or NNIs). Code named U-90152, it is a type of NNRTI known as the bis(heteroaryl)piperazines or BHAPs.
NNRTIs are extraordinarily specific for HIV RT, but they have a major drawback: resistant viral populations arise quickly and confer resistance to other types of NNRTIs. BHAPs like delavirdine are of particular interest in resistance studies because they tend to elicit a Pro236-Leu mutation that confers resistance to BHAPs but that makes the virus more sensitive to other NNRTIs.
Oxford University researcher Robert M. Esnouf and colleagues performed a series of structural analyses of the delavirdine/HIV-1 RT complex.
"The structure allows prediction of binding modes for related inhibitors [(alkylamino)piperidine-BHAPs (AAP-BHAPs)] and suggests changes to U-90152 [delavirdine] such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT," Esnouf et al. wrote.
Esnouf et al. reported their findings in the Proceedings of the National Academy of Sciences ("Unique Features in The Structure of The Complex between HIV-1 Reverse Transcriptase and The Bis(heteroaryl)piperazine (BHAP) U-90152 Explain Resistance Mutations for This Nonnucleoside Inhibitor," PNAS, 1997;94:3984-9).
The analysis indicated that the AAP-BHAPs may, in some ways, have better anti-RT activity than delavirdine.
Upjohn researchers R.A. Olmsted and colleagues reported the development of AAP-BHAPs in 1996 (J Virol, 1996;70:3698- 705).
The two most potent of these compounds are dubbed U-95133 and U-104489. Perhaps more exciting than their potent anti- HIV activity is their ability to inhibit mutant HIV-1 strains bearing the NNRTI resistance mutation (Tyr181-to-Cys) at submicromolar concentrations.
U-104489 was also able to inhibit HIV-1 bearing the BHAP resistance mutation (Pro236-to-Leu) as well as viral strains resistant to delavirdine and zidovudine (AZT).
HIV-1 resistant to AAP-BHAPs carries the Gly190-to-Glu substitution. But this mutation, Olmsted et al. noted, "had a deleterious effect on the integrity and enzymatic activity of virion-associated reverse-transcriptase heterodimers, as well as the replication capacity of these resistant viruses."
The Esnouf et al. structural analysis indicated that delavirdine has a highly desirable property: it is stabilized by hydrogen bonding and extensive hydrophobic contacts within the RT "pocket" in which NNRTIs act.
"The novel hydrogen bonding pattern observed between the protein and the NNI U-90152 [delavirdine] may be quite a general vehicle for generating binding affinity that is less susceptible to point mutations," Esnouf et al. suggested. "It seems likely that such interactions could be engineered into other inhibitor complexes, perhaps with quite different chemistry."
This project has received the long-term support of the Medical Research Council of Great Britain AIDS-Directed Program.
The corresponding author for this study is David I. Stuart, Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford, OX1 3QU, United Kingdom.
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