Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-12-22
1999-03-23
Smith, Lynette F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
4241881, 4241841, 4242081, 4242041, 530350, 530395, C07H 2102, C07K 100, C07K 1400, A61K 3921
Patent
active
058861637
DESCRIPTION:
BRIEF SUMMARY
The life cycle of animal viruses is characterized by a series of events that are required for the productive infection of the host cell. The initial step in the replicative cycle is the attachment of the virus to the cell surface, which attachment is mediated by the specific interaction of the viral attachment protein (VAP) to receptors on the surface of the target cell. The differential pattern of expression of these receptors is largely responsible for the host range and tropic properties of viruses. In addition, an effective immune response against many viruses is mediated through neutralizing antibodies directed against the VAP. The interaction of the VAP with cellular receptors and the immune system therefore plays a critical role in infection and pathogenesis of viral disease.
The human immunodeficiency virus type 1 (HIV-1) infects primarily helper T lymphocytes, dendritic cells, and monocytes/macrophages--cells that express surface CD4--leading to a gradual loss of immune function. This loss of function results in the development of the human acquired immunodeficiency syndrome (AIDS) (1). The initial phase of the HIV-1 replicative cycle involves the high-affinity interaction between the HIV-1 exterior envelope glycoprotein gp120 and cell surface CD4 (K.sub.d approximately 4.times.10.sup.-9 M) (2). Several lines of evidence demonstrate the requirement of this interaction for viral infectivity. The introduction into CD4.sup.- human cells of cDNA encoding CD4 is sufficient to render otherwise resistant cells susceptible to HIV-1 infection (3). In vivo, viral infection appears to be restricted to cells expressing CD4, indicating that the cellular tropism of HIV-1 is largely determined by the pattern of cellular expression of CD4. Following the binding of HIV-1 gp120 to cell surface CD4, viral and target cell membranes fuse by a mechanism that is poorly understood, resulting in the introduction of the viral capsid into the target cell cytoplasm (4).
Mature CD4 has a relative molecular mass (Mr) of 55 kDa and consists of an N-terminal 372-amino acid extracellular domain containing four tandem immunoglobulin-like regions (V1-V4), followed by a 23-amino acid transmembrane domain and a 38-amino acid cytoplasmic segment (5, 6). In experiments using truncated sCD4 proteins, it has been shown that the determinants for high-affinity binding to HIV-1 gp120 lie solely within the N-terminal immunoglobulin-like domain V1) (7-9). Mutational analysis of V1 has defined a discrete binding site (residues 38-52) that comprises a region structurally homologous to the second complementarity-determining region (CDR2) of immunoglobulin genes (9).
The production of large quantities of sCD4 has permitted a structural analysis of the two N-terminal immunoglobulin-like domains (V1V2). The structure determined at 2.3 angstrom resolution reveals that the molecule has two tightly-associated domains, each of which contains the immunoglobulin-fold connected by a continuous beta strand. The putative binding sites for monoclonal antibodies, class II major histocompatibility complex (MHC) molecules, and HIV-1 gp120, as determined by mutational analyses, map on the molecular surface (10, 11).
The HIV-1 envelope gene env encodes an envelope glycoprotein precursor, gp160, which is cleaved by cellular proteases before transport to the plasma membrane to yield gp120 and gp41. The membrane-spanning glycoprotein, gp41, is non-covalently associated with gp120, a purely extracellular glycoprotein. The mature gp120 molecule is heavily glycosylated (approximately 24 N-linked oligosaccharides), contains approximately 480 amino acid residues with 9 intrachain disulfide bonds (12), and projects from the viral membrane as a dimeric or multimeric molecule (13).
Mutational studies of HIV-1 gp120 have delineated important functional regions of the molecule. The regions of gp120 that interact with gp41 map primarily to the N- and C-termini (14). The predominant strain-specific neutralizing epitope on gp120 is located in the 32-34 amino acid residue third v
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Hasel Karl W.
Maddon Paul J.
Progenics Pharmaceuticals Inc.
Smith Lynette F.
White John P.
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