Prospects of HIV-1 entry inhibitors as novel therapeutics.

A great deal of progress has been made in understanding the mechanism of human immunodeficiency virus entry into target cells. Landmark discoveries such as the identification of viral coreceptors and the structure of a portion of the viral envelope protein (Env) bound to its receptor provided important insight into how Env mediates fusion of the viral and cellular membranes. This knowledge has been successfully applied to the development of inhibitors that target discrete steps of the entry process. Some of these compounds efficiently block HIV-1 replication in vitro and are currently being evaluated in clinical trials. In this review, we will introduce the challenges of antiviral therapy and highlight the need for novel therapeutics, such as entry inhibitors, to complement current antiviral regimens. The mechanism by which Env mediates HIV-1 entry and the therapeutic potential of small molecule inhibitors of this dynamic process will be discussed in detail. Copyright 2004 John Wiley & Sons, Ltd.