New Agents for the Inhibition of HIV Replication

Abstract

Reprinted with permission from www.hivresistance.com (May 1, 2000). S everal groups are in the process of developing new drugs that inhibit the entry of HIV into cells as well as the integration of HIV into genomic DNA. Unfortunately for many of our most desperate patients, such agents are not yet ready for prime time. Perhaps the most promising of these compounds are two oral drugs, one from Schering-Plough and one from Merck. These candidates both inhibit the binding of HIV to CCR5 on monocytes and T-cells. According to Baroudy and colleagues at Schering, their lead candidate for an inhibitor blocks CCR5 dependent entry, is orally bioavailable, has a favorable pharmacokinetic profile in animals, and does not inhibit cytochrome p450.1 Early phase I trials are planned for later this year. It is important to point out that the development of both of these agents is unlikely to be affected by the wholesale licensing of life as we know it by Human Genome Sciences and other pathetic corporate denizens. Research also continues on antibody-based approaches to entry blocking (PRO 140) and fusion inhibitors (T-20 and bicyclams). Trkola and colleagues at the Aaron Diamond AIDS Research Center and researchers at Progenics reported that the monoclonal antibody PRO 140 was potent, durable, and widely effective against CCR5-dependent viruses.2 It must be pointed out, however, that for our patients, this may not be the approach we want. Studies of mixtures of viruses show that exposure to subtherapeutic concentrations of CCR5 inhibitors leads to rapid evolution of CCR5-independent viruses. Moreover, judging from human studies, these non-CCR5-dependent viruses tend to be more aggressive and somewhat more resistant to nucleoside drugs and other antiretrovirals. In this regard, inhibitors of CXCR4-dependent viruses may actually be more important. This is where protegrin, tachyplesin drugs, and bicyclams may have a role. As reported by De Clercq and coworkers, bicyclams inhibit the entry of viruses that utilize CXCR4 as well as viruses that use both CCR5 and CXCR4.3 As a result, AMD3100, their lead compound, might be a “safer” HIV therapeutic, as viruses that “escape” would be, it is presumed, predominantly CCR5 utilizing viruses. Only time will tell if this strategy works. Clinical trials are planned for fourth quarter of 2000. New Agents for the Inhibition of HIV Replication