Computer-assisted anti-AIDS drug development: cyclophilin B against the HIV-1 subtype A V3 loop

Alexander M. Andrianov, Ivan V. Anishchenko

.

DOI: 10.4236/health.2010.27100                

Abstract

Aim: The objects of this study originated from the experimental observations, whereby the HIV -1 gp120 V3 loop is a high-affinity ligand for immunophilins, and consisted in generating the structural complex of cyclophilin (Cyc) B belonging to immunophilins family with the virus subtype A V3 loop (SA-V3 loop) as well as in specifying the Cyc B segment forming the binding site for V3 synthetic copy of which, on the assumption of keeping the 3D peptide structure in the free state, may present a forwardlooking basic structure for anti-AIDS drug development. Methods: To reach the objects of view, molecular docking of the HIV-1 SA-V3 loop structure determined previously with the X-ray conformation of Cyc B was put into practice by Hex 4.5 program (http://www.loria.fr/~ritchied/ hex/) and the immunophilin stretch responsible for binding to V3 (Cyc B peptide) was identified followed by examination of its 3D structure and dynamic behavior in the unbound status. To design the Cyc B peptide, the X-ray conformation for the identical site of the native protein was involved in the calculations as a starting model to find its best energy structural variant. The search for this most preferable structure was carried out by consecutive use of the molecular mechanics and simulated annealing methods. The molecular dynamics computations were implemented for the Cyc B peptide by the GROMACS computer package (http:// www.gromacs.org/). Results: The overmolecular structure of Cyc B with V3 was built by computer modeling tools and the immunophilinderived peptide able to mask effectively the structurally invariant V3 segments embracing the functionally crucial amino acids of the HIV-1 gp120 envelope protein was constructed and analyzed. Conclusions: Starting from the joint analysis of the results derived with those of the literature, the generated peptide was suggested to offer a promising basic structure for making a reality of the protein engineering projects aimed at developing the anti-AIDS drugs able to stop the HIV’s spread.

Keywords

HIV-1; V3 Loop; Cyclophilin B; Computer Modeling; Molecular Docking; Anti-Aids Drug Design

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Gallo, R.C. and Montagnier, L. (2003) The discovery of HIV as the cause of AIDS. The New England Journal of Medicine, 349(24), 2283-2285.
[2]	Wyatt, R. and Sodroski, J. (1998) The HIV-1 envelope glycoproteins: Fusogens, antigens, and immunogens. Science, 280(5371), 1884-1888.
[3]	Landau, N.R., Warton, M. and Littman, D.R. (1988) The envelope glycoprotein of the human immunodeficiency virus binds to the immunoglobulin-like domain of CD4. Nature, 334(6178), 159-162.
[4]	Feng, Y., Broder, C.C., Kennedy, P.E. and Berger, E.A. (1996) HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science, 272(5263), 872-877.
[5]	Deng, H., Liu, R., Ellmeier, W., Choe, S., Unutmaz, D., Burkhart, M., Di Marzio, P., Marmon, S., Sutton, R.E., Hill, C.M., Davis, C.B., Peiper, S.C., Schall, T.J., Littman, D.R. and Landau, N.R. (1996) Identification of a Major Co-Receptor for Primary Isolates of HIV-1. Nature, 381(6584), 661-666.
[6]	Sirois, S., Sing, T. and Chou, K.C. (2005) HIV-1 gp120 V3 loop for structure-based drug design. Current Protein & Peptide Science, 6(5), 413-422.
[7]	Hartley, O., Klasse, P.J., Sattentau, Q.J. and Moore J.P. (2005) V3: HIVs Switch-Hitter. AIDS Research and Human Retroviruses, 21(8), 171-189.
[8]	Hwang, S.S., Boyle, T.J., Lyerly, H.K. and Cullen, B.R. (1991) Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science, 253(5015), 71-74.
[9]	Choe, H., Farzan, M., Sun, Y., Sullivan, N., Rollins, B., Ponath, P.D., Wu, L., Mackay, C.R., LaRosa, G., Newman, W., Gerard, N., Gerard, C. and Sodroski, J. (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell, 85(7), 11351148.
[10]	Cocchi, F., DelVico, A., Garzino-Demo, A., Cara, A., Gallo, R.C. and Lusso, P. (1996) The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nature Medicine, 2(11), 1244-1247.
[11]	Connor, R.I., Sheridan, K.E., Ceradini, D., Choe, S. and Landau, N.R. (1997) Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. The Journal of Experimental Medicine, 185(4), 621-628.
[12]	Scarlatti, G., Tresoldi, E., Bjorndal, A., Fredriksson, R., Colognesi, C., Deng, H.K., Malnati, M.S., Plebani, A., Siccardi, A.G., Littman, D.R., Fenyo, E.M. and Lusso, P. (1997) In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nature Medicine, 3(11), 1259-1265.
[13]	Endrich, M.M. and Gehring, H. (1998) The V3 loop of human immunodeficiency virus type-1 envelope protein is a high-affinity ligand for immunophilins present in human blood. European Journal of Biochemistry, 252(3), 441-446.
[14]	Galat, A. and Metcalfe, S.M. (1995) Peptidylproline cis/trans isomerases. Progress in Biophysics and Molecular Biology, 63(1), 67-118.
[15]	Barik, S. (2006) Immunophilins: For the love of proteins. Cellular and Molecular Life Sciences, 63(24), 28892900.
[16]	Baker, E.K., Colley, N.J. and Zuker, C.S. (1994) The cyclophilin homolog NinaA functions as a chaperone, forming a stable complex in vivo with its protein target rhodopsin. The EMBO Journal, 13(20), 4886-4895.
[17]	Ferreira, P.A., Nakayama, T.A. and Travis, G.H. (1997) Interconversion of red opsin isoforms by the cyclophilinrelated chaperone protein Ran-binding protein 2. Proceedings of the National Academy of Sciences, USA, 94(4), 1556-1561.
[18]	Hacker, J. and Fischer, J. (1993) Immunophilins: structure-function relationship and possible role in microbial pathogenicity. Molecular Microbiology, 10(3), 445-456.
[19]	Moro, A., Ruiz-Cabello, F., Fernandez-Cano, A., Stock, R. P. and Gonzalez, A. (1995) Secretion by Trypanosoma cruzi of a peptidyl-prolyl cis-trans isomerase involved in cell infection. The EMBO Journal, 14(11), 2483-2490.
[20]	Spik, G., Haendler, B., Delmas, O., Mariller, C., Chamoux, M., Maes, P., Tartar, A., Montreuil, J., Stedman, K., Kocher, H.P., Keller, R., Hiestand, P.C. and Movva, N.R. (1991) A novel secreted cyclophilin-like protein (SCYLP). Journal of Biological Chemistry, 266(17), 10735-10738.
[21]	Allain, F., Boutillon, C., Mariller, C. and Spik, G. (1995) Selective assay for CyPA and CyPB in human blood using highly specific anti-peptide antibodies. Journal of Immunological Methods, 178(1), 113-120.
[22]	Endrich, M. M., Grossenbacher, D., Geistlich, A. and Gehring, H. (1996) Apoptosis-induced concomitant release of cytosolic proteins and factors which prevent cell death. Biology of the Cell, 88(1-2), 15-22.
[23]	Sherry, B., Yarlett, N., Strupp, A. and Cerami, A. (1992) Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proceedings of the National Academy of Sciences, USA, 89(8), 3511-3515.
[24]	Xu, Q., Leiva, M.C., Fischkoff, S.A., Handschumacher, R.E. and Lyttle, C.R. (1992) Leukocyte chemotactic activeity of cyclophilin. The Journal of Biological Chemistry, 267(17), 11968-11971.
[25]	Bang, M., Muller, W., Hans, M., Brune, K., Swandulla, D. (1995) Activation of Ca2+ signaling in neutrophils by the mast cell-released immunophilin FKBP12. Proceedings of the National Academy of Sciences, USA, 92(8), 3435-3438.
[26]	Saphire, A.C.S., Bobardt, M.D. and Gallay, P.A. (1999) Host cyclophilin A mediates HIV-1 attachment to target via heparans. The EMBO Journal, 18(23), 6771-6785.
[27]	Franke, E.K., Yuan, H.E.H. and Luban, J. (1994) Specific incorporation of cyclophhilin a into HIV-1 virions. Nature, 372(6504), 359-362.
[28]	Thali, M., Bukovsky, A., Kondo, E., Rosenwirth, B., Walsh, C.T., Sodroski, J. and Gottlinger, H.G. (1994) Functional association of cyclophilin A with HIV-1 virions. Nature, 372(6504), 363-365.
[29]	Colgan, J., Yuan, H.E.H., Franke, E.K. and Luban, J. (1996) Binding of the human immunodeficiency virus type 1 Gag polyprotein to cyclophilin A is mediated by the central region of capsid and requires Gag dimerization. The Journal of Virology, 70(7), 4299-4310.
[30]	Andrianov, A.M. (2008) Computational anti-AIDS drug design based on the analysis of the specific interactions between immunophilins and the HIV-1 gp120 V3 loop. Application to the FK506-binding protein. Journal of Biomolecular Structure & Dynamics, 26(1), 49-56.
[31]	Andrianov, A.M. (2009) Immunophilins and HIV-1 V3 loop for structure-based anti-AIDS drug design. Journal of Biomolecular Structure & Dynamics, 26(4), 445-454.
[32]	Andrianov A.M. and Anishchenko I.V. (2009) Computational model of the HIV-1 subtype A V3 loop: Study on the conformational mobility for structure-based antiAIDS drug design. Journal of Biomolecular Structure & Dynamics, 27(2), 179-194.
[33]	Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E. F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M. (1997) The protein data bank. A computer-based archival file for macromolecular structures. Journal of Molecular Biology, 112(3), 535-542.
[34]	Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E. (2000) The Protein Data Bank. Nucleic Acids Research, 28(1), 235-242.
[35]	Mustard, D. and Ritchie, D.W. (2005) Macromolecular docking using spherical polar fourier correlations. Proteins: Structure, Function, and Bioinformatics, 60(2), 269-274.
[36]	Berendsen, H.J.C., van der Spoel, D. and van Drunen, R. (1995) GROMACS: A message-passing parallel molecular dynamics implementation. Computer Physics Communications, 91(1-3), 43-56.
[37]	Mikol, V., Kallen, J. and Walkinshaw, M.D. (1994) X-ray structure of a Cyclophilin B/Cyclosporin complex: Comparison with Cyclophilin A and delineation of its calcineurin-binding domain. Proceedings of the National Academy of Sciences, 91(11), 5183-5186.
[38]	Ren, P. and Ponder, J.W. (2003) TINKER: Software tools for molecular design. The Journal of Biological Chemistry, 107, 59335947.
[39]	Oostenbrink, C., Villa, A., Mark, A.E. and van Gunsteren, W.F. (2004) A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6. The Journal of Biological Chemistry, 25(13), 1656-1676.
[40]	Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F. and Hermans, J. (1981) Interaction models for water in relation to protein hydration. In: B. Pullman Ed., Intermolecular Forces, Dordrecht: D. Reidel Publishing Company, Boston, pp. 331-342.
[41]	Berendsen, H.J.C., Postma, J.P.M., DiNola, A. and Haak, J.R. (1984) Molecular-dynamics with coupling to an external bath. Journal of Chemical Physics, 81(8), 36843690.
[42]	Ablameyko, S.V., Abramov, S.M., Anishchanka, U.V., Medvedev, S.V., Paramonov, N.N. and Tchij, O.P. (2005) SKIF supercomputer configurations (in Russian). Minsk, United Institute of Informatics Problems.
[43]	Smith, L.J., Bolin, K.A., Schwalbe, H., MacArthur, M. W., Thornton, J.M. and Dobson, C.M. (1996) Analysis of main chain torsion angles in proteins: Prediction of NMR coupling constants for native and random coil conformations. Journal of Molecular Biology, 255(3), 494-506.
[44]	Hutchinson, E.G. and Thornton, J.M. (1996) PROMOTIF—a program to identify and analyze structural motifs in proteins. Protein Science, 5(2), 212-220.
[45]	Sherman, S.A. and Johnson, M.E. (1993) Derivation of locally accurate spatial protein structure from NMR data. Progress in Biophysics and Molecular Biology, 59(3), 285339.
[46]	Cormier, E.G. and Dragic, T. (2002) The crown and the stem V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with CCR5 coreceptor. The Journal of Virology, 76(17), 8953-8957.
[47]	LaRosa, G.J., Davide, J.P., Weinhold, K., Waterbury, J.A., Profy, A.T., Lewis, J.A., Langlois, A.J., Dressman, G.R., Boswell, R.N., Shadduk, P., Holley, L.H., Karplus, M., Bolognesi, D.P., Matthews, T.J., Emini, E.A. and Putney, S.D. (1990) Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant. Science, 249(4971), 932-935.
[48]	Ivanoff, L.A., Looney, D.J., McDanal, C., Morris, J.F., Wong-Staat, F., Lang, A.J., Petteway, S.R.Jr. and Matthews, T.J. (1991) Alteration of HIV-1 infectivity and neutralization by a single amino acid replacement in the V3 loop domain. AIDS Research and Human Retroviruses, 7(7), 595-603.
[49]	Minder, D., Boni, J., Schupbach, J. and Gering, H. (2002) Immunophilins and HIV-1 infection. Archives of Virology, 147(8), 1531-1542.
[50]	Wang, W.-K., Dudek, T., Zhao, Y.-J., Brumblay, H.G., Essex, M. and Lee, T.-H. (1998) CCR5 coreceptor utilization involves a highly conserved arginine residue of HIV type 1 gp120. Proceedings of the National Academy of Sciences, USA, 95(10), 5740-5745.
[51]	de Parseval, A., Bobardt, M.D., Chatterji, U., Elder, J.H., David, G., Zolla-Pazner, S., Farzan, M., Lee, T.H. and Gallay, P.A. (2005) A highly conserved arginine in gp120 governs HIV-1 binding to both syndecans and CCR5 via sulfated motifs. The Journal of Biological Chemistry, 280(47), 39493-39504.
[52]	Hu, Q., Napier, K.B., Trent, J.O., Wang, Z., Taylor, S., Griffin, G.E., Peiper, S.C. and Shattock, R.J. (2005) Restricted variable residues in the C-terminal segment of HIV-1 V3 loop regulate the molecular anatomy of CCR5 utilization. Journal of Molecular Biology, 350(4), 699712.
[53]	Ghiara, J.B., Stura, E.A., Stanfield, R.L., Profy, A.T. and Wilson, I.A. (1994) Crystal structure of the principal neutralization site of HIV-1. Science, 264(5155), 82-85.
[54]	Chavda, S.C., Griffin, P., Han-Liu, Z., Keys, B., Vekony, M.A. and Cann, A.J. (1994) Molecular determinants of the V3 loop of human immunodeficiency virus type 1 glyco-protein gp120 responsible for controlling cell tropism. Journal of General Virology, 75(11), 3249-3253.
[55]	Mammano, F., Salvatori, F., Ometto, L., Panozzo, M., Chieco-Bianchi, L. and De Rossi, A. (1995) Relationship between the V3 loop and the phenotypes of human immunodeficiency virus type 1 (HIV-1) isolates from children perinatally infected with HIV-1. The Journal of Virology, 69(1), 82-92.
[56]	Milich, L., Margolin, B.H. and Swanstrom, R. (1993) v3 loop of the human immunodeficiency virus type 1 env protein: Interpreting sequence variability. The Journal of Virology, 67(9), 5623-5634.
[57]	Shioda, T., Levy, J.A. and Cheng-Mayer, C. (1992) Small amino acid changes in the V3 hypervariable region of gp120 can affect the T-cell-line and macrophage tropism of human immunodeficiency virus type 1. Proceedings of the National Academy of Sciences, 89(20), 9434-9438.
[58]	Wu, L., Gerard, N.P., Wyatt, R., Choe, H., Parolin, C., Ruffin, N., Borsetti, A., Cardoso, A.A., Desjardin, E., Newman, Gerard, W.C. and Sodroski, J. (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature, 384(6605), 179-183.
[59]	Fouchier, R.A.M., Groenink, M., Kootstra, N.A., Tersmette, M., Huisman, H.G., Miedema, F. and Schuitemaker, H. (1992) Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. The Journal of Virology, 66(5), 3183-3187.
[60]	De Jong, J.J., De Ronde, A., Keulen, W., Tersmette, M. and Goudsmit, J. (1992) Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: Analysis by single amino acid substitution. The Journal of Virology, 66(11), 6777-6780.
[61]	Ogert, R.A., Lee, M.K., Ross, W., Buckler-White, A., Martin, M.A. and Cho, M.W. (2001) N-linked glycosylation sites adjacent to and within the V1/V2 and the V3 loops of dualtropic human immunodeficiency virus type 1 isolate DH12 gp120 affect coreceptor usage and cellular tropism. The Journal of Virology, 75(13), 5998-6006.
[62]	Smith, J.A. and Pease, L.J. (1980) Reverse turns in peptides and proteins. Critical Reviews in Biochemistry, 8(4), 315-399.
[63]	Rose, G.D., Gierasch, L.M. and Smith, J.A. (1985) Turns in peptides and proteins. Advances in Protein Chemistry, 37, 1-109.
[64]	Newton, A.C. (2001) Protein kinase C: Structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chemical Reviews, 101(8), 2353-2364.