Summary
CCR5 (CC-chemokine receptor 5) is a key co-receptor, in concert with CD4, for infectivity of HIV-1 (human immunodeficiency virus type-1) into healthy human cells, and RANTES, an endogenous ligand for CCR5, is a potent inhibitor of HIV-1 infectivity. In this structure-activity relationship (SAR) study, peptide fragments derived from RANTES were designed, synthesized and evaluated for their ability to inhibit HIV-1 infectivity. The goal was to determine the effect of peptide length on anti-HIV activity and to obtain an optimally sized RANTES peptide probe for further SAR studies. The analogue Ac[Ala10,11]RANTES-(1–14)NH2, AA14, was identified as an effective inhibitor of HIV-1 infectivity at 10 nM but despite the functional activity, surprisingly it did not exhibit any notable affinity for the CCR5 chemokine receptor. Further, increasing peptide size enhanced neither the inhibition of HIV-1 infectivity nor CCR5 receptor affinity. As a potent inhibitor of HIV-1 infectivity, the lead analogue most likely utilizes a different (and currently unknown) mechanism than interaction with CCR5 for anti-HIV activity.
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Abbreviations
- BSA:
-
bovine serum albumin
- CHO:
-
Chinese hamster ovary
- CCR5:
-
CC-chemokine receptor5
- CPM:
-
counts per minute
- DIEA:
-
N,N-diisopropylethylamine
- DMF:
-
N,N-dimethylformamide
- ELISA:
-
enzyme-linked immunosorbent assay
- FBS:
-
fetal bovine serum
- Fmoc-PAL-PEG-PS resin:
-
Nα-9-fluorenylmethoxycarbonyl-5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid-polyethylene glycol-polystyrene resin
- HATU:
-
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- HIV-1:
-
human immunodeficiency virus type-1
- ID50 :
-
50% infectious dilution
- MIP:
-
macrophage inflammatory protein
- Mobile phase A:
-
0.1% (v/v) TFA in HPLC grade water
- Mobile phase B:
-
0.1% (v/v) TFA in either acetonitrile or methanol
- PBS:
-
phosphate buffered saline
- RANTES:
-
regulated upon activation, normal T-cell expressed and secreted
- RPHPLC:
-
reverse phase high performance liquid chromatography
- SAR:
-
structure-activity relationship
- TCID50 :
-
50% tissue culture infective dose
- TFA:
-
trifluoroacetic acid
References
Murphy, P. M., Annu. Rev. Immunol., 12 (1994) 593.
Schall, T. J., Cytokine, 3 (1991) 165.
Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C. and Lusso, P., Science, 270 (1995) 1811.
Palker, T. J., Clark, M. E., Langlois, A. J., Matthews, T. J., Weinhold, K. J., Randall, R. R., Bolognesi, D. P. and Haynes, B. F., Proc. Natl. Acad. Sci. USA, 85 (1988) 1932.
Pinter, A., Honnen, W. J. and Tilley, S. A., J. Virol., 67 (1993) 5692.
Sattentau, Q. J. and Moore, J. P., J. Exp. Med., 174 (1991) 407.
Speck, R. F., Wehrly, K., Platt, E. J., Atchison, R. E., Charo, I. F., Kabat, D., Chesebro, B. and Goldsmith, M. A., J. Virol., 71 (1997) 7136.
Wu, L., Gerard, N. P., Wyatt, R., Choe, H., Parolin, C., Ruffing, N., Borsetti, A., Cardoso, A. A., Desjardin, E., Newman, W., Gerard, C. and Sodroski, J., Nature, 384 (1996) 179.
Trkola, A., Dragic, T., Arthos, J., Binley, J. M., Olson, W. C., Allaway, G. P., Cheng-Mayer, C., Robinson, J., Maddon, P. J. and Moore, J. P., Nature, 384 (1996) 184.
Amara, A., Gall, S. L., Schwartz, O., Salamero, J., Montes, M., Loetscher, P., Baggiolini, M., Virelizier, J. L. and Arenzana-Seisdedos, F., J. Exp. Med., 186 (1997) 139.
Alkhatib, G., Locati, M., Kennedy, P. E., Murphy, P. M. and Berger, E. A., Virology, 234 (1997) 340.
Hayashi, S., Kurdowska, A., Miller, E. J., Albright, M. E., Girten, B. E. and Cohen, A. B., J. Immunol., 154 (1995) 814.
Kawai, M., Quincy, D. A., Lane, B., Mollison, K. W., Luly, J. R. and Carter, G. W., J. Med. Chem., 34 (1991) 2068.
Nishiyama, Y., Murakami, T., Kurita, K. and Yamamoto, N., Chem. Pharm. Bull. (Tokyo), 45 (1997) 2125.
Nishiyama, Y., Murakami, T., Kurita, K. and Yamamoto, N., Bioorg. Med. Chem. Lett., 49 (1999) 1357.
Nishiyama, Y., Murakami, T., Shikama, S., Kurita, K. and Yamamoto, N., Bioorg. Med. Chem. Lett., 10 (2002) 4113.
Chung, C. W., Cooke, R. M., Proudfoot, A. E. I. and Wells, T. N. C., Biochemistry, 34 (1995) 9307.
Solé, N. A. and Barany, G., J. Org. Chem., 57 (1995) 5399.
Lusso, P., Cocchi, F., Balotta, C., Markham, P. D., Louie, A., Farci, P., Pal, R., Gallo, R. C. and Reitz, M. S., J. Virol., 69 (1995) 3712.
Wu, S. C., Spouge, J. L., Conley, S. R., Tsai, W. P., Merges, M. J. and Nara, P. L., J. Virol., 69 (1995) 6054.
Spouge, J. L., Proc. Natl. Acad. Sci. USA, 89 (1992) 7581.
Wells, T. N. C., Proudfoot, A. E. I., Power, C. A., Lusti-Narasimhan, M., Alouani, S., Hoogewerf, A. J. and Pietsch, M. C., METHODS: A Companion toMethods in Enzymology, 10 (1996) 126.
Wells, T. N., Powers, C. A., Lusti-Narasimhan, M., Hoogewerf, A. J., Cooke, R. M., Chung, C. W., Peitsch, M. C. and Proudfoot, A. E., J. Leukoc. Biol., 59 (1996) 53.
Polo, S., Nardese, V., DeSantis, C., Arcelloni, C., Paroni, R., Sironi, F., Verani, A., Rizzi, M., Bolognesi, M. and Lusso, P., Eur. J. Immunol., 30 (2000) 3190.
Atchison, R. E., Gosling, J., Monteclaro, F. S., Franci, C., Digilio, L., Charo, I. F. and Goldsmith, M. A., Science, 274 (1996) 1924.
Gosling, J., Monteclaro, F. S., Atchison, R. E., Arai, H., Tsou, C. L., Goldsmith, M. A. and Charo, I. F., Proc. Natl. Acad. Sci. USA, 94 (1997) 5061.
Ylisastigui, L., Vizzavona, J., Drakopoulou, E., Paindavoine, P., Calvo, C. F., Parmentier, M., Gluckman, J. C., Vita, C. and Benjouad, A., AIDS, 12 (1998) 977.
Wells, T. N., Guye-Coulin, F. and Bacon, K. B., Biochem. Biophys. Res. Commun., 4211 (1995) 100.
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Ramnarine, E., DeVico, A.L. & Vigil-Cruz, S.C. A synthetic peptide fragment derived from RANTES is a potent inhibitor of HIV-1 infectivity despite a surprising lack of CCR5 receptor affinity. Int J Pept Res Ther 10, 637–643 (2003). https://doi.org/10.1007/s10989-005-3969-7
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DOI: https://doi.org/10.1007/s10989-005-3969-7