Wiggling and Jiggling Can Increase the Effectiveness of AIDS Drugs

Janssen PAJ, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Béthune M-P, Pauwels R, Das K, Clark AD Jr, Volovik Frenkel Y, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, and Stoffels P. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]-2-pyrimidinyl]amino]benz-onitrile (R278474, rilpivirine). J Med Chem 48: 1901–9, 2005.

Das K, Clark AD Jr, Lewi PJ, Heeres J, de Jonge MR, Koymans LMH, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, de Béthune M-P, Boyer PL, Clark P, Hughes SH, Janssen PAJ, and Arnold E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 47: 2550–60, 2004.

Lewi PJ, de Jonge M, Daeyaert F, Koymans L, Vinkers M, Heeres J, Janssen PA, Arnold E, Das K, Clark AD Jr, Hughes SH, Boyer PL, de Béthune MP, Pauwels R, Andries K, Kukla M, Ludovici D, De Corte B, Kavash R, and Ho C. On the detection of multiple-binding modes of ligands to proteins, from biological, structural, and modeling data. J Comput Aided Mol Des 17: 129–34, 2003.

lthough great progress has been made in the treatment of HIV-1/AIDS, treatment failures still occur. One of the primary causes of HIV-1 treatment failure is the emergence of drug-resistant viral variants. Because HIV-1 evolves so rapidly in patients, finding drugs that can consistently hit this “moving target” is a major challenge.

There are four classes of drugs used to treat HIV-1 infections: fusion inhibitors, protease inhibitors, and two types of drugs that inhibit the viral enzyme reverse transcriptase (RT)—nucleoside analogs and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Unfortunately, HIV-1 can become resistant to all the available drugs. However, it is more difficult for the virus to develop resistance to some drugs than to others. One of the critical goals in combating treatment failure is to develop new drugs that will present the greatest possible challenge to viral resistance. When new drugs are developed, it is particularly important that they are effective and potent against resistant viruses that already exist. In the case of the NNRTIs, the ability of the drug to bind tightly to both the wild-type and drug-resistant RTs is a key design consideration.

The compound TMC125-R165335 (etravirine) is a very promising NNRTI currently being tested in patients in the United States. Etravirine was developed through a multidisciplinary effort involving chemical synthesis, tests of drug candidates against both wild-type and drug-resistant HIV-1 strains, structure determination by X-ray crystallography, and molecular modeling. Crystal structures were determined for candidate NNRTIs in complexes with both wild-type and drug-resistant forms of RT. The crystal structures provided the templates for extensive molecular modeling that guided the synthesis of new NNRTIs, which led to the discovery of etravirine and related diarylpyrimidine (DAPY) compounds.

In a recent study published in J Med Chem (47: 2550–60, 2004), Das and colleagues described the structural work behind the discovery of the DAPY compounds and discussed how the conformational flexibility of the molecules, together with their ability to reposition themselves within the drug-binding pocket, allows them to bind effectively to, and inhibit, both the wild-type and drug-resistant RTs. These two complementary properties (which the authors describe as “wiggling” and “jiggling”) allow etravirine and other DAPY compounds to bind to the many different forms of the drug-binding pocket that are found in drug-resistant RTs. This recent work is supported by the molecular modeling calculations of Lewi and colleagues (J Comput Aided Mol Des 17: 129–34, 2003), which suggested that NNRTIs with multiple binding modes would be better able to inhibit drug-resistant RTs.

Figure 1. Wiggling and jiggling allow a nonnucleoside reverse transcriptase inhibitor (NNRTI) to effectively inhibit drug-resistant HIV-1 reverse transcriptase. The figure shows, in cartoon form, a comparison of the binding of a rigid inhibitor that cannot reposition itself in the drug-binding pocket and a flexible inhibitor that can reposition itself. Mutations in the drug-binding pocket change the shape of the pocket, causing steric hindrance that interferes with the binding of the rigid inhibitor (left side of the cartoon). An inhibitor that can adapt its shape (wiggling) and binding position (jiggling) in response to the changes in the binding pocket can still bind effectively to mutant drug-binding pockets (right side).

A drug like etravirine, which can wiggle and jiggle, is able to bind to and inhibit mutant forms of RT that can evade a more rigid NNRTI, which cannot effectively reposition itself and bind tightly to the altered drug-binding pockets of drug-resistant RTs (Figure 1). Das and colleagues proposed that the approach of designing drugs that adapt their structure and binding modes to counteract variation in their binding sites should be applicable to other HIV-1 targets, as well as to targets in other rapidly evolving organisms, including other viruses and bacteria.

Even though etravirine is an exceptionally promising drug, the search for new drugs that can be used in the treatment of AIDS (including additional NNRTIs) continues. Another promising NNRTI in the same family as etravirine is R278474, described in the paper by Janssen et al. (J Med Chem 48: 1901–9, 2005). Although the testing of this new compound is not complete, the compound has been very potent in short-term phase II clinical trials.

Stephen H. Hughes, PhD
Chief, Retroviral Replication Laboratory
HIV Drug Resistance Program
NCI-Frederick, Bldg. 539/Rm. 130A
Tel: 301-846-1619
Fax: 301-846-6966
hughes@ncifcrf.gov

back to top