HIV-1 Entry Inhibitors in the Side Pocket

transmembrane envelope glycoproteins. Most of the exJoseph G. Sodroski Department of Cancer Immunology and AIDS posed surface of the assembled trimer is composed of Dana-Farber Cancer Institute elements of gp120, with the gp41 ectodomain largely Department of Pathology buried in the interior of the complex (Figure 1, left panel). Harvard Medical School and The gp120 glycoprotein binds the host cell receptors, Department of Immunology and Infectious Diseases whereas gp41 is thought to be responsible for fusing the Harvard School of Public Health viral and target cell membranes. The gp41 ectodomain Boston, Massachusetts 02115 must therefore be exposed to the target cell membrane in a controlled fashion, when the virus has achieved adequate proximity to the cell. Receptor binding not only attaches and orients the viral envelope glycoproteins to Several years ago, investigators made the serendipitous the target cell, but also triggers conformational changes discovery that peptides corresponding to segments of in the envelope glycoproteins that promote the sethe human immunodeficiency virus (HIV-1) gp41 envequence of events leading to membrane fusion. The nalope glycoprotein could specifically and potently inhibit ture of these conformational changes is imperfectly unvirus entry into target cells (Wild et al., 1992; Jiang et derstood, as structural information is available on only al., 1993). Subsequently, the emergence of structural a single conformation of gp120 (Kwong et al., 1998) and information on the HIV-1 envelope glycoproteins algp41 (Chan et al., 1997; Tan et al., 1997; Weissenhorn lowed insights into the mechanism by which these pepet al., 1997). CD4 binding has been shown to induce tides exert their antiviral effect. In addition to their use a gp120 conformation that is able to bind the CCR5 as tools to understand the process of HIV-1 entry, these chemokine receptor with high affinity. A model in which peptides serve as a starting point for the development chemokine receptor binding then results in the exposure of potentially useful therapeutics. of the gp41 ectodomain is appealing, although the availHIV-1 Entry able supporting data (Furuta et al., 1998) exhibit some HIV-1 enters cells through the interaction of its envelope inconsistencies. For example, similar effects on gp41 glycoproteins with cellular receptors, CD4 and chemoexposure were observed for both the CCR5 and CXCR4 kine receptors (for review, see Chan and Kim, 1998; chemokine receptors, even though only one of these Wyatt and Sodroski, 1998). Following receptor binding, coreceptors supported gp120 binding and virus entry the envelope glycoproteins fuse the viral membrane with of the HIV-1 strains tested. Furthermore, the envelope the target cell membrane, allowing entry of the viral core glycoproteins of some HIV-1 strains exhibited the same into the host cell cytoplasm. Each envelope glycoprotein gp41 exposure after binding only CD4, whereas chemospike on the viral surface consists of a trimer of three gp120 exterior envelope glycoproteins and three gp41 kine receptor binding is necessary for the efficient entry