Abstract: The invention provides for compounds of formula I: wherein Z is absent or (CRARB)nW; each RA and RB is independently (i) H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, each of which may be optionally substituted; (ii) OH, ORc, NH2, NHRc, NRcRc, SH, S(O)mRc; or (iii) RA and RB together form C(O); W is absent, C(O), C(O)O, C(O)NRcRc, O, S(O)m, or NRcRc; Y is an optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted aryl, or NRXRY; wherein Rx and Ry are each independently H, alkyl or aryl; X1 is selected from the group consisting of halogen, methyl, and hydroxyl; X2 is a halogen; each Rc is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which may be optionally substituted; m is O, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; and pharmaceutically acceptable salts thereof.

Abstract: Described herein are methods of generating a protein binding domain that specifically binds to gp120 in a specific conformational state, comprising contacting gp120 with a CD4-mimetic compound, thereby forming gp120 in the specific conformational state; and generating antibodies to gp120 in the specific conformation state. Relatedly, the disclosure also describes methods of neutralizing HIV-1, comprising contacting HIV-1 with an effective amount of a CD4-mimetic compound, thereby forming HIV-1 having gp120 in a specific conformational state; and contacting the HIV-1 in the specific conformational state with an antibody.

Abstract: Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gp120, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD-556.

Abstract: Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gp120, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD-556.

Abstract: This invention provides two soluble polypeptides which comprise a portion of CD4 comprising all HIV gp120-binding epitopes present on intact CD4, wherein the polypeptide has a cysteine substitution at a residue which, in intact CD4, interfaces with HIV gp120. This invention also provides a method for making a derivatized soluble polypeptide and a method for obtaining a structural model useful in the design of an agent for inhibiting CD4 binding to HIV gp120.

Abstract: This invention provides methods for producing a membrane-bound protein in mammalian cells. This invention also provides nucleic acids for making novel fusion proteins (e.g., GPCR fusion proteins). This invention further provides related bacterial expression vectors; expression methods; fusion proteins; bacterial cells; GPCR vector screens; bacterial spheroplasts; methods for making anti-GPCR antibodies; and GPCR binding screens. This invention also provides a method for identifying a reagent in which a membrane protein is likely to crystallize. Finally, this invention provides methods for producing crystals of a protein which, in a cell, is a membrane-bound protein.

Abstract: A modified polypeptide corresponding to an envelope glycoprotein of a primate lentivirus is described. The polypeptide has been modified from the wild-type structure so that it has cysteine amino acid residues introduced to create disulfide bonds, a cavity is filled with hydrophobic amino acids, a Proresidue is introduced at a defined turn structure of the protein, or the hydrophobicity is increased across the interface between different domains, while retaining the overall 3-dimensional structure of a discontinuous conserved epitope of the wild-type protein. Preferably, the polypeptide has more than one of those characteristics. Preferably, the primate lentivirus is HIV, and the protein is HIV-1 gp120.

Abstract: A modified polypeptide corresponding to an envelope glycoprotein of a primate lentivirus is described. The polypeptide has been modified from the wild-type structure so that it has at least two of the glycosylation sites proximal to the CD4 binding site or chemokine receptor site altered so that the alteration prevents glycosylation at that site or where glycosylation sites distal to these sites have been derivatized with a molecular adjuvant, while retaining the overall 3-dimensional structure of a discontinuous conserved epitope of the wild-type protein. Preferably, the polypeptide has both changes. Preferably, the primate lentivirus is HIV, and the protein is HIV-1 gp 120.

Abstract: This invention provides a computer based method for preparing a stem cell factor (SCF) analog comprising the steps of: (a) providing computer expression of the three dimensional structure of an SCF molecule using its crystal structure; (b) selecting from the computer expression of step (a) at least one site on the SCF molecule for alteration; (c) preparing a SCF molecule having an alteration at said at least one selected site; and (d) optionally, testing the SCF molecule for a desired characteristic. This invention also provides SCF analogs and SCF ligand analogs prepared according to the above-described method. Compositions comprising SCF analogs or SCF ligand analogs prepared according to the above-described method effective to treat a subject and a pharmaceutically acceptable carrier are provided, as are methods of treating a subject comprising administration of pharmaceutical compositions comprising the prepared SCF analogs and SCF ligand analogs prepared by the described methods.

Abstract: A process for determination of three-dimensional macromolecular atomic structures of proteins is provided. A plurality of gene products are clustered into at least one family of homologous sequences. At least one protein encoded by a sequence selected from each of the families is prepared, purified and characterized. The purified proteins are crystallized in parallel against crystallization screens. Diffraction data produced by the crystallized proteins is measured using a multi-wavelength anomalous diffraction method. The diffraction data is analyzed by using a multi-wavelength anomalous diffraction phasing method, an atomic model is built, and the model is refined based on the diffraction data to determine a three-dimensional macromolecular atomic structure for each of the crystallized proteins.

Abstract: This invention provides a method for identifying a compound which inhibits HIV-1 entry into a cell. This invention also provides a compound which inhibits the cavity binding interaction between HIV-1 gp120 and CD4. This invention further provides a method of inhibiting HIV-1 infection of a cell, a method of preventing HIV-1 infection in a subject and a method of treating HIV-1 infection in a subject comprising contacting the cell or administering to the subject an amount of the compound which inhibits the cavity binding interaction between HIV-1 gp120 and CD4 effective to inhibit HIV-1 infection, thereby inhibiting HIV-1 infection of the cell, preventing HIV-1 infection in the subject and treating HIV-1 infection in the subject.

Abstract: A process for pan-genomic determination of three-dimensional macromolecular atomic structures uses a unique combination of components. All known structural information, sequence information and functional information are systematically organized into a genomics database. Advanced tools of bioinformatics are used to cluster all known gene products into families of homologous sequences. Simultaneously, in parallel for each such family, a few cDNAs from appropriately representatives species are cloned into expression vectors for a few expressions systems. Constructs are then screened for expression, and those that are effective advance to the preparative step. Expressed proteins are prepared, purified and characterized. Purified proteins are set to crystallize in parallel against crystallization screens. Crystals that grow are tested for suitable diffraction characteristics.

Abstract: This invention provides a non-naturally occurring targeted lipolytic compound comprising a lipolytic agent linked to a targeting agent. In an embodiment, the lipolytic agent is covalently attached to the targeting agent. In an embodiment, the lipolytic agent is a phospholipase and the targeting agent is a viral receptor. This invention further provides for therapeutic uses of the non-naturally occurring targeted lipolytic compound. In an embodiment, the non-naturally occurring targeted lipolytic compound neutralizes virions of the human immunodeficiency virus (HIV).

Abstract: This invention provides a non-naturally occurring targeted lipolytic compound comprising a lipolytic agent linked to a targeting agent. In an embodiment, the lipolytic agent is covalently attached to the targeting agent. In an embodiment, the lipolytic agent is a phospholipase and the targeting agent is a viral receptor. This invention further provides for therapeutic uses of the non-naturally occurring targeted lipolytic compound. In an embodiment, the non-naturally occurring targeted lipolytic compound neutralizes virions of the human immunodeficiency virus (HIV).

Abstract: A process pan-genomic determination of three-dimensional macromolecular atomic structures uses a unique combination of components.