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Inhibition of in Vitro and in Vivo HIV Replication by a Distamycin Analogue That Interferes with Chemokine Receptor Function:  A Candidate for Chemotherapeutic and Microbicidal Application

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Intramural Research Support Program, Anti-AIDS Virus Drug Screening Laboratory, and Laboratory of Antiviral Drug Mechanisms, SAIC Frederick, and Laboratory of Molecular Immunoregulation, Division of Basic Science, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892, Department of Pharmacology and Vermont Cancer Center, University of Vermont, Burlington, Vermont 05405, Southern Research Institute-Frederick Research Center, 431 Aviation Way, Frederick, Maryland 21702
Cite this: J. Med. Chem. 1998, 41, 13, 2184–2193
Publication Date (Web):June 3, 1998
Copyright © 1998 American Chemical Society

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    Select chemokine receptors act as coreceptors for HIV-1 entry into human cells and represent targets for antiviral therapy. In this report we describe a distamycin analogue, 2,2‘-[4,4‘-[[aminocarbonyl]amino]bis[N,4‘-di[pryrrole-2-carboxamide-1,1‘-dimethyl]]-6,8-naphthalenedisulfonic acid]hexasodium salt (NSC 651016), that selectively inhibited chemokine binding to CCR5, CCR3, CCR1, and CXCR4, but not to CXCR2 or CCR2b, and blocked chemokine-induced calcium flux. Inhibition was not due to nonspecific charge interactions at the cell surface, but was based on a specific competition for the ligand receptor interaction sites since the inhibitory effect was specific for some but not all chemoattractant receptors. NSC 651016 inhibited in vitro replication of a wide range of HIV-1 isolates, as well as HIV-2 and SIV, and exhibited in vivo anti-HIV-1 activity in a murine model. In contrast, a distamycin analogue with similar structure and charge and the monomeric form of NSC 651016 demonstrated no inhibitory effects. These data demonstrate that molecules which interfere with HIV-1 entry into cells by targeting specific chemokine coreceptors can provide a viable approach to anti-HIV-1 therapy. NSC 651016 represents an attractive candidate for the chemotherapeutic treatment of HIV-1 infection and as a microbicide to prevent the sexual transmisssion of HIV-1. Moreover, NSC 651016 can serve as a template for medicinal chemical modifications leading to more effective antivirals.

     Intramural Research Support Program, NCI-FCRDC.

     Laboratory of Molecular Immunoregulation, NCI-FCRDC.


     Developmental Therapeutics Program, NCI.

     University of Vermont.

     Southern Research Institute-FRC.

     Anti-AIDS Virus Drug Screening Laboratory, NCI-FCRDC.


     Laboratory of Antiviral Drug Mechanisms, NCI-FCRDC.


     Corresponding author:  William G. Rice, Ph.D., Sr. Scientist and Head, Laboratory of Antiviral Drug Mechanisms, National Cancer Institute-Frederick Cancer research and Development Center, SAIC Frederick, Building 431 T-B, P.O. Box B, Frederick, MD 21702-1201; Phone (301) 846-5060; FAX (301)846-6846; E-mail rice@

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    3. Harshil R. Shah, Jignasa Ketan Savjani. Recent updates for designing CCR5 antagonists as anti-retroviral agents. European Journal of Medicinal Chemistry 2018, 147 , 115-129.
    4. S. S. Zykova, A. R. Galembikova, B. R. Ramazanov, T. F. Odegova, N. M. Igidov, M. A. Kiselev, S. V. Boichuk. Synthesis and Cytotoxic Activity of Ethyl 2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)- 4,5-Dihydro-1H-Pyrrole-3-Carboxylates. Pharmaceutical Chemistry Journal 2016, 49 (12) , 817-820.
    5. S. S. Zykova, A. A. Darovskikh, T. F. Odegova, M. A. Kiselev, N. M. Igidov. Synthesis and Pharmacological Activity of Ethyl-2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)Pyrrolidine-3-Carboxylates. Pharmaceutical Chemistry Journal 2016, 49 (10) , 657-660.
    6. Francesca Sironi, Mauro Malnati, Nicola Mongelli, Paolo Cozzi, Christina Guzzo, Silvia Ghezzi, Carles Martínez-Romero, Adolfo García-Sastre, Paolo Lusso, Daniela Jabes, Priscilla Biswas. Characterization of HIV-1 entry inhibitors with broad activity against R5 and X4 viral strains. Journal of Translational Medicine 2015, 13 (1)
    7. Luis Menéndez-Arias, Mar Álvarez. Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Research 2014, 102 , 70-86.
    8. Wanwan Yu, Wenteng Chen, Shen Liu, Jiaan Shao, Zhanying Shao, Haili Lin, Yongping Yu. Facile, eco-friendly, catalyst-free synthesis of polyfunctionalized 2-aminopyrroles. Tetrahedron 2013, 69 (7) , 1953-1957.
    9. Alexey V. Dobrydnev, Tatyana A. Volovnenko, Yulian M. Volovenko, Gennady V. Palamarchuk, Oleg V. Shishkin. Cyclic α-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones and their spiro derivatives. Monatshefte für Chemie - Chemical Monthly 2012, 143 (5) , 779-789.
    10. E. O. Baranova, N. S. Shastina, V. I. Shvets. Polyanionic inhibitors of HIV adsorption. Russian Journal of Bioorganic Chemistry 2011, 37 (5) , 527-542.
    11. Tomohiro Tanaka, Tetsuo Narumi, Taro Ozaki, Akira Sohma, Nami Ohashi, Chie Hashimoto, Kyoko Itotani, Wataru Nomura, Tsutomu Murakami, Naoki Yamamoto, Hirokazu Tamamura. Azamacrocyclic Metal Complexes as CXCR4 Antagonists. ChemMedChem 2011, 6 (5) , 834-839.
    12. Tetsuo Narumi, Ryoko Hayashi, Kenji Tomita, Kazuya Kobayashi, Noriko Tanahara, Hiroaki Ohno, Takeshi Naito, Eiichi Kodama, Masao Matsuoka, Shinya Oishi, Nobutaka Fujii. Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres. Org. Biomol. Chem. 2010, 8 (3) , 616-621.
    13. Ayhan S. Demir, Mustafa Emrullahoğlu, Kerem Buran. Gold(i)/Zn(ii) catalyzed tandem hydroamination/annulation reaction of 4-yne-nitriles. Chemical Communications 2010, 46 (42) , 8032.
    14. Ya Zhuo, Ren Kong, Xiao-jing Cong, Wei-zu Chen, Cun-xin Wang. Three-dimensional QSAR analyses of 1,3,4-trisubstituted pyrrolidine-based CCR5 receptor inhibitors. European Journal of Medicinal Chemistry 2008, 43 (12) , 2724-2734.
    15. Hirokazu Tamamura, Hiroshi Tsutsumi, Wataru Nomura, Tomohiro Tanaka, Nobutaka Fujii. A future perspective on the development of chemokine receptor CXCR4 antagonists. Expert Opinion on Drug Discovery 2008, 3 (10) , 1155-1166.
    16. Antonio Mastrolorenzo, Alfonso Maresca, Stefano Rusconi, Claudiu T Supuran. Update on the development of HIV entry inhibitors. Future HIV Therapy 2008, 2 (5) , 479-507.
    17. Hirokazu Tamamura, Hiroshi Tsutsumi, Wataru Nomura, Nobutaka Fujii. Exploratory Studies on Development of the Chemokine Receptor CXCR4 Antagonists toward Downsizing. Perspectives in Medicinal Chemistry 2008, 2 , PMC.S422.
    18. Priscilla Biswas, Giuseppe Tambussi, Adriano Lazzarin. Access denied? The status of co-receptor inhibition to counter HIV entry. Expert Opinion on Pharmacotherapy 2007, 8 (7) , 923-933.
    19. Hiroshi Tsutsumi, Tomohiro Tanaka, Nami Ohashi, Hiroyuki Masuno, Hirokazu Tamamura, Kenichi Hiramatsu, Takanobu Araki, Satoshi Ueda, Shinya Oishi, Nobutaka Fujii. Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents. Peptide Science 2007, 88 (2) , 279-289.
    20. Priscilla Biswas, Silvia Nozza, Gabriella Scarlatti, Adriano Lazzarin, Giuseppe Tambussi. Oral CCR5 inhibitors: will they make it through?. Expert Opinion on Investigational Drugs 2006, 15 (5) , 451-464.
    21. Ayhan S. Demir, Mustafa Emrullahoglu. Zinc perchlorate catalyzed one-pot amination–annulation of α-cyanomethyl-β-ketoesters in water. Regioselective synthesis of 2-aminopyrrole-4-carboxylates. Tetrahedron 2006, 62 (7) , 1452-1458.
    22. Hirokazu Tamamura, Nobutaka Fujii. The therapeutic potential of CXCR4 antagonists in the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Expert Opinion on Therapeutic Targets 2005, 9 (6) , 1267-1282.
    23. Ayhan S. Demir, Mustafa Emrullahoglu. An effective new synthesis of 2-aminopyrrole-4-carboxylates. Tetrahedron 2005, 61 (44) , 10482-10489.
    24. A. V. Tverdokhlebov, A. B. Lyashenko, Yu. M. Volovenko, A. A. Tolmachev. Synthesis of 5-amino-4-hetaryl-2,3-dihydro-1h-3-pyrrolones. Chemistry of Heterocyclic Compounds 2004, 40 (12) , 1536-1542.
    25. Pier Giovanni Baraldi, Andrea Bovero, Francesca Fruttarolo, Delia Preti, Mojgan Aghazadeh Tabrizi, Maria Giovanna Pavani, Romeo Romagnoli. DNA minor groove binders as potential antitumor and antimicrobial agents. Medicinal Research Reviews 2004, 24 (4) , 475-528.
    26. Raymond Reeves, Dale Edberg. HMGA proteins: multifaceted players in nuclear function. 2004, 155-180.
    27. Minghu Song, Curt M. Breneman, N. Sukumar. Three-dimensional quantitative structure–activity relationship analyses of piperidine-based CCR5 receptor antagonists. Bioorganic & Medicinal Chemistry 2004, 12 (2) , 489-499.
    28. Jim A Turpin. The next generation of HIV/AIDS drugs: novel and developmental antiHIV drugs and targets. Expert Review of Anti-infective Therapy 2003, 1 (1) , 97-128.
    29. Maria Elena Fuentes, Tara Mirzadegan, Robert S. Wilhelm. Chemokine and Cytokine Modulators. 2003, 119-192.
    30. Jim A Turpin. Considerations and development of topical microbicides to inhibit the sexual transmission of HIV. Expert Opinion on Investigational Drugs 2002, 11 (8) , 1077-1097.
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    32. Hirokazu Tamamura, Kenichi Hiramatsu, Kazuhide Miyamoto, Akane Omagari, Shinya Oishi, Hideki Nakashima, Naoki Yamamoto, Yoshihiro Kuroda, Terumichi Nakagawa, Akira Otaka, Nobutaka Fujii. Synthesis and evaluation of pseudopeptide analogues of a specific CXCR4 inhibitor, T140: The insertion of an (E)-alkene dipeptide isostere into the βII′-turn moiety. Bioorganic & Medicinal Chemistry Letters 2002, 12 (6) , 923-928.
    33. Yulian M. Volovenko, Anton V. Tverdokhlebov, Alexandr P. Gorulya, Svetlana V. Shishkina, Roman I. Zubatyuk, Oleg V. Shishkin. A New and Convenient Synthesis of 1,2-Diamino-3-hetarylpyrrole Derivatives. European Journal of Organic Chemistry 2002, 2002 (4) , 663-668.<663::AID-EJOC663>3.0.CO;2-A
    34. Amanda E. I. Proudfoot. Chemokine receptors: multifaceted therapeutic targets. Nature Reviews Immunology 2002, 2 (2) , 106-115.
    35. Rita Cortesi, Claudio Nastruzzi. Delivery systems for DNA-binding drugs as gene expression modulators. Drug Discovery Today 2001, 6 (17) , 893-904.
    36. Tatjana Dragic. An overview of the determinants of CCR5 and CXCR4 co-receptor function. Journal of General Virology 2001, 82 (8) , 1807-1814.
    37. Hirokazu Tamamura, Akane Omagari, Kenichi Hiramatsu, Taisei Kanamoto, Kazuyo Gotoh, Kenji Kanbara, Naoki Yamamoto, Hideki Nakashima, Akira Otaka, Nobutaka Fujii. Synthesis and evaluation of bifunctional anti-HIV agents based on specific CXCR4 antagonists-AZT conjugation. Bioorganic & Medicinal Chemistry 2001, 9 (8) , 2179-2187.
    38. Hirokazu Tamamura, Akane Omagari, Kenichi Hiramatsu, Kazuyo Gotoh, Taisei Kanamoto, Younong Xu, Eiichi Kodama, Masao Matsuoka, Toshio Hattori, Naoki Yamamoto, Hideki Nakashima, Akira Otaka, Nobutaka Fujii. Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140. Bioorganic & Medicinal Chemistry Letters 2001, 11 (14) , 1897-1902.
    39. Lokesh Agrawal, Ghalib Alkhatib. Chemokine receptors: emerging opportunities for new anti-HIV therapies. Expert Opinion on Therapeutic Targets 2001, 5 (3) , 303-326.
    40. Hirokazu Tamamura, Makiko Sugioka, Yoshihiko Odagaki, Akane Omagari, Yukiko Kan, Shinya Oishi, Hideki Nakashima, Naoki Yamamoto, Stephen C Peiper, Nobuyuki Hamanaka, Akira Otaka, Nobutaka Fujii. Conformational study of a highly specific CXCR4 inhibitor, T140, disclosing the close proximity of its intrinsic pharmacophores associated with strong anti-HIV activity. Bioorganic & Medicinal Chemistry Letters 2001, 11 (3) , 359-362.
    41. Alexandra Trkola, Thomas J. Ketas, Kirsten A. Nagashima, Lu Zhao, Tonie Cilliers, Lynn Morris, John P. Moore, Paul J. Maddon, William C. Olson. Potent, Broad-Spectrum Inhibition of Human Immunodeficiency Virus Type 1 by the CCR5 Monoclonal Antibody PRO 140. Journal of Virology 2001, 75 (2) , 579-588.
    42. Sonia L. Holz-Smith, I-Chen Sun, Lei Jin, Thomas J. Matthews, Kuo-Hsiung Lee, Chin Ho Chen. Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564. Antimicrobial Agents and Chemotherapy 2001, 45 (1) , 60-66.
    43. Jim A Turpin, OM Zack Howard. Inhibitors of HIV cellular fusion. Expert Opinion on Therapeutic Patents 2000, 10 (12) , 1899-1909.
    44. Hirokazu Tamamura, Akane Omagari, Shinya Oishi, Taisei Kanamoto, Naoki Yamamoto, Stephen C Peiper, Hideki Nakashima, Akira Otaka, Nobutaka Fujii. Pharmacophore identification of a specific CXCR4 inhibitor, T140, leads to development of effective anti-HIV agents with very high selectivity indexes. Bioorganic & Medicinal Chemistry Letters 2000, 10 (23) , 2633-2637.
    45. David H. McDermott, Philip M. Murphy. Chemokines and their receptors in infectious disease. Springer Seminars in Immunopathology 2000, 22 (4) , 393-415.
    46. John P. Moore, Mario Stevenson. New targets for inhibitors of HIV-1 replication. Nature Reviews Molecular Cell Biology 2000, 1 (1) , 40-49.
    47. Bao Qun Li, Tao Fu, Wang-Hua Gong, Nancy Dunlop, Hsiang-fu Kung, Yaodong Yan, Jian Kang, Ji Ming Wang. The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines. Immunopharmacology 2000, 49 (3) , 295-306.
    48. Nobutoki Takamune, Shogo Misumi, Shozo Shoji. Cyclic Zinc-Dithiocarbamate-S,S′-Dioxide Blocks CXCR4-Mediated HIV-1 Infection1. Biochemical and Biophysical Research Communications 2000, 272 (2) , 351-356.
    49. Wade S Blair, Pin-Fang Lin, Nicholas A Meanwell, Owen B Wallace. HIV-1 entry – an expanding portal for drug discovery. Drug Discovery Today 2000, 5 (5) , 183-194.
    50. Richard Horuk, Howard P. Ng. Chemokine Receptor Antagonists. Medicinal Research Reviews 2000, 20 (2) , 155-168.<155::AID-MED3>3.0.CO;2-G
    51. Sergio A. Lira, Paul J. Zavodny, Daniel Lundell. Chemokines. 2000, 121-138.
    52. Tomas Cihlar, Norbert Bischofberger. Chapter 16. Recent developments in antiretroviral therapies. 2000, 177-189.
    53. Ji Ming Wang, Joost J. Oppenheim. Interference with the Signaling Capacity of Cc Chemokine Receptor 5 Can Compromise Its Role as an HIV-1 Entry Coreceptor in Primary T Lymphocytes. The Journal of Experimental Medicine 1999, 190 (5) , 591-596.
    54. O. M. Zack Howard, Aiko-Konno Shirakawa, Jim A. Turpin, Andrew Maynard, Gregory J. Tobin, Mary Carrington, Joost J. Oppenheim, Michael Dean. Naturally Occurring CCR5 Extracellular and Transmembrane Domain Variants Affect HIV-1 Co-receptor and Ligand Binding Function. Journal of Biological Chemistry 1999, 274 (23) , 16228-16234.
    55. William C. Olson, Gwénaël E. E. Rabut, Kirsten A. Nagashima, Diep N. H. Tran, Deborah J. Anselma, Simon P. Monard, Jeremy P. Segal, Daniah A. D. Thompson, Francis Kajumo, Yong Guo, John P. Moore, Paul J. Maddon, Tatjana Dragic. Differential Inhibition of Human Immunodeficiency Virus Type 1 Fusion, gp120 Binding, and CC-Chemokine Activity by Monoclonal Antibodies to CCR5. Journal of Virology 1999, 73 (5) , 4145-4155.
    56. Nick Cammack. Human Immunodeficiency Virus Type 1 Entry and Chemokine Receptors: A New Therapeutic Target. Antiviral Chemistry and Chemotherapy 1999, 10 (2) , 53-62.
    57. Edward A. Berger, Philip M. Murphy, Joshua M. Farber. CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease. Annual Review of Immunology 1999, 17 (1) , 657-700.
    58. Pius Loetscher, Bernhard Moser, Marco Baggiolini. Chemokines and Their Receptors in Lymphocyte Traffic and HIV Infection. 1999, 127-180.
    59. Hirokazu Tamamura, Younong Xu, Toshio Hattori, Xiaoyan Zhang, Rieko Arakaki, Kenji Kanbara, Akane Omagari, Akira Otaka, Toshiro Ibuka, Naoki Yamamoto, Hideki Nakashima, Nobutaka Fujii. A Low-Molecular-Weight Inhibitor against the Chemokine Receptor CXCR4: A Strong Anti-HIV Peptide T140. Biochemical and Biophysical Research Communications 1998, 253 (3) , 877-882.

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