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August 21, 2006
Volume 84, Number 34
p. 9


Retaining Efficacy Against Evasive HIV

Darunavir analog to AIDS-virus shapeshifters: Resistance may be futile

Stu Borman

In work that is not yet published, an analog of a recently approved AIDS drug has shown a unique and extraordinary property: no loss of potency whatsoever when confronted with multi-drug-resistant (MDR) strains of human immunodeficiency virus (HIV).



The analog, called GRL-02031, is one of several variations on the new drug darunavir. Together these agents could be a prototype for a new class of medicines that address one of the most serious weaknesses of current AIDS drugs—their tendency to lose effectiveness when HIV mutates into MDR forms.

Darunavir was discovered by professor of chemistry and medicinal chemistry Arun K. Ghosh of Purdue University and coworkers. They used structure-based design to create an HIV protease inhibitor that would retain nearly full activity against MDR virus, relative to its potency with wild-type virus. Darunavir was provisionally approved in June by the Food & Drug Administration for use in combination therapy by patients unresponsive to existing AIDS drugs. Trade named Prezista, it is marketed by Tibotec Therapeutics, Bridgewater, N.J.

Ghosh and coworkers next discovered GRL-06579A, in which darunavir's key bioactive group, a bis-tetrahydrofuran, is replaced with a cyclic ether (J. Med. Chem., 2006, 49, 5252). Like darunavir, GRL-06579A maintains most of its potency against MDR strains, but it may last longer than darunavir in the body. GRL-02031, which retains all its potency, represents their latest advance. They will not reveal the structure of GRL-02031 until it???s reported in the literature.


CHECKMATE X-ray structure shows darunavir (stick structure) bound primarily to the active-site backbone (red and yellow ribbon structure) of HIV protease. Yellow dotted lines are hydrogen-bond interactions with the backbone (protein chain); white ones are hydrogen bonds to side chains. Darunavir retains most of its efficacy against MDR virus because the active-site backbone is structurally nearly invariant in different strains.

Ghosh's main collaborator on the studies is virologist Hiroaki Mitsuya of the National Cancer Institute, the discoverer of three other approved AIDS drugs, including the first, zidovudine (AZT). Principal funding was provided by the National Institute of General Medical Sciences (NIGMS).

"Darunavir potentially resets the goals in treatment for patients with advanced disease, especially MDR HIV infection," says Jeffrey P. Nadler, assistant director of the Therapeutics Research Program in the Division of AIDS at the National Institute of Allergy & Infectious Diseases. "What we don't have are long-term results, and that will await full approval." If an analog like GRL-02031 ???turns out to be cleaner than other protease inhibitors in terms of side effects and long-term toxicity, to retain darunavir's clinical activity, and to be more ???resistance resistant,' it would represent a real advance in protease therapy."

The discovery of darunavir and its analogs was based on 1994 findings by Ghosh and coworkers that the backbone (main chain) of HIV protease's active-site amino acids remains structurally nearly invariant in different strains, whereas the side chains do vary. "Their approach is to design molecules that interact preferentially with the backbone and other conserved features of the protease," says NIGMS Director Jeremy M. Berg. "There's presumably nothing the enzyme can do to avoid the inhibitor without disrupting interactions with its substrates and therefore losing activity."

Ghosh says he's happy that people may live longer as a result of his team's discoveries. He and his coworkers hope to tweak the structure of darunavir analogs still further and perhaps eventually submit one for clinical testing.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2010 American Chemical Society