Reports have appeared recently on agents that are active against several new targets in the HIV life cycle. These are:
- Rev inhibitors
- Zinc finger inhibitors
Rev is a regulatory protein which permits the movement of newly manufactured viral RNA from the nucleus of an infected cell to the cytoplasm, where it can co-opt cellular machinery to produce HIV proteins. The presence of rev is essential for this transportation to occur.
Guanidinoglycosides are a modified form of the antibiotic group called aminoglycosides. These antibiotics have been used to treat gram negative bacterial infections, but have proved ineffective against HIV until now. In two reports published last month, researchers from the University of California, San Diego, showed that guanidoglycosides inhibited rev activity, the first time that an agent targeting this site has been shown to have a potent inhibitory effect. These in vitro studies will allow further studies in animal models to be carried out, to test the anti-HIV effect of these compounds. At present the guanidoglycosides are not being developed by a pharmaceutical company.
ADA - new zinc finger inhibitor
HIV’s zinc fingers are chains of amino acids found in HIV’s nucleocapsid, a core viral protein. They are involved in binding and packaging viral RNA into new virions budding from an infected cell, and may also play a role in the process of reverse transcription. Experiments in which HIV’s zinc fingers have been deleted have shown that viruses without zinc fingers are unable to infect new cells, and that any new virus particles that they produce do not incorporate the viral RNA and are thus non-infectious and dysfunctional.
Azodicarbonamide (ADA) is a zinc finger inhibitor. In a report published in the January 5 edition of AIDS, Dr Frank Goebel of Munich's Ludwig-Maximilians-Universitat showed that ADA treatment in a group of 15 individuals with advanced HIV disease and virological failure on current HAART was associated with a significant viral load reduction when added to failing therapy.
An initial open label phase escalated the dosage monthly, from 1g tid to 3g tid over three months.
The phase I/II study was not specifically designed to test efficacy, and treated a very small number of patients, but a clear relationship between introduction of ADA treatment, withdrawal of treatment, suppression and subsequent rebound of viral load was demonstrated, despite failing background therapy. Declines of 0.5 log to 1.2 log and corresponding rebounds were observed after starting and withdrawing treatment in three of five individuals who received ADA in a subsequent open label phase.
CD4 cell count improvements were also noted in the open label phase of the study. CD4 counts increased by an average of 120 cells after three months.
A number of drawbacks have been identified with this drug:
- Nephrolithiasis: three discontinuations due to renal pain or high levels of creatinine, all caused by the breakdown of ADA into biurea
- Dose related glucose intolerance was observed (only two patients had elevated glucose levels at baseline, but fasting glucose increased significantly in all patients by month three of ADA treatment, and declined after ADA was withdrawn). ADA may interfere with the formation of insulin.
- ADA needs to be re-formulated to improve absorption, so that lower doses may be given, thereby reducing the risk of some of these side effects
ADA is being developed by a Belgian company, Hubriphar, in collaboration with the Rega Institute, Leuven.
Reference
Baker T et al. Synthesis and Anti-HIV Activity of GuanidinoglycosidesJournal of Organic Chemistry 65 (26): 9054-9058, 2000.
Goebel FD et al. Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy. AIDS 15: 33-45, 2000.
Kirk S et al. Neomycin-Acridine Conjugate: A Potent Inhibitor of Rev-RRE Binding. Journal of the American Chemical Society 122(5); 980-981, 2000.