Anti-HIV-1 Activity of the Iboga Alkaloid Congener 18-Methoxycoronaridine

Abstract

The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC₅₀ values of 22.5 ± 4.7 μM and 23 ± 4.5 μM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC₅₀ equal to 12.8 ± 5 μM and 9.5 ± 3 μM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC₅₀ = 69.4 μM), which at least partially explains its antiretroviral activity.

HIV-1 - AIDS - 18-methoxycoronaridine - Iboga alkaloid - reverse transcriptase

References

• 1 WHO / UNAIDS. Global summary of the HIV/AIDS epidemic. December 2003 www.unaids.org
• 2 Berger E A, Murphy P M, Farber J M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.  Ann Rev Immunol. 1999;  17 657-700
• 3 Pantaleo G, Graziosi C, Demarest J F, Butini L, Montroni M, Fox C H, Orestein J M, Kotler D P, Fauci A. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease.  Nature. 1993;  362 355-8
• 4 Pallela Jr F J, Delaney K M, Moorman A C, Loveless M O, Fuhrer J, Satten G A, Aschman D J, Holmberg S D. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  New Engl J Med. 1998;  338 853-60
• 5 Blankson J N, Persaud D, Siliciano R. The challenge of viral reservoir in HIV-1 infection.  Annu Rev Med. 2002;  53 557-93
• 6 Richman D D. HIV chemotherapy.  Nature. 2001;  410 995-1001
• 7 Condra J H, Miller M D, Hazuda D J, Emini E A. Potential new therapies for the treatment of HIV-1 infection.  Annu Rev Med. 2002;  53 541-55
• 8 Maisonneuve I M, Glick S D. Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.  Pharmacol Biochem Behav. 2003;  75 607-18
• 9 Glick S D, Maisonneuve I M, Szumlinski K K. 18-Methoxycoronaridine (18-MC) and ibogaine. Comparison of antiaddictive efficacy, toxicity and mechanisms of action.  Ann N Y Acad Sci. 2000;  914 369-86
• 10 Delorenzi J C, Attias M, Gattass C R, Andrade M, Rezende C, Pinto A C, Henriques A T, Bou-Habib D C, Saraiva E MB. Antileishmanial activity of an indole alkaloid from Peschiera australis .  Antimicrob Agents Chemother. 2001;  45 1349-54
• 11 Delorenzi J C, Freire-de-Lima L, Gattass C R, Costa D, He A L, Kuehne M E, Saraiva E MB. In vitro activities of iboga alkaloid congeners coronaridine and 18-methoxycoronaridine against Leishmania amazonensis .  Antimicrob Agents Chemother. 2002;  46 2111-5
• 12 Vlietinck A J, De Bruyne T, Apers S, Pieters L A. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection.  Planta Medica. 1998;  64 97-109
• 13 Brazilian Network for HIV Isolation and C haracterization. HIV-1 diversity in Brazil: genetic, biologic, and immunologic characterization of HIV-1 strains in three potential HIV vaccine evaluation sites.  J Acquir Immune Defic Syndr. 2000;  23 184-93
• 14 Ferraro G A, Mello M AG, Sutmoller F, Van Weyenberg J, Brazilian Network for HIV Isolation and C haracterization, Shindo N, Galvão-Castro B, Bou-Habib D C. Biological characterization and chemokine receptor usage of HIV type 1 isolates prevalent in Brazil.  AIDS Res Hum Retroviruses . 2001;  17 1241-7
• 15 Bandarage U K, Kuehne M E, Glick S D. Total synthesis of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine.  Tetrahedron. 1999;  55 9405-24
• 16 Da Matta A D, Santos C VE, Pereira H S, Frugulhetti I CPP, Oliveira M RP, Souza M CBV, Moussatché N, Ferreira V F. Synthesis of novel nucleosides of 4-oxoquinoline-3-carboxylic acid analogues.  Heteroatom Chemistry. 1999;  10 197-202
• 17 McMahon J B, Currens M J, Gulakowski R J, Bucheit R W, Lackman-Smith C, Hallock Y F, Boyd M R. Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms.  Antimicrob Agents Chemother. 1995;  39 484-8
• 18 Tan G T, Kinghorn A D, Hughes S H, Pezzuto J M. Psychotrine and its O-methyl ether are selective inhibitors of human immunodeficiency virus-1 reverse transcriptase.  J Biol Chem. 1991;  266 23 529-36
• 19 Walker B D, Kowalski M, Goh W C, Kozarsky K, Krieger M, Rosen C, Rohrschneider L, Haseltine W A, Sodroski J. Inhibition of human immunodeficiency virus syncytium formation and virus replication by castanospermine.  Proc Natl Acad Sci USA. 1987;  84 8120-4
• 20 Chao C C, Gekker G, Sheng W S, Hu S, Peterson P K. U50488 inhibits HIV-1 expression in acutely infected monocyte-derived macrophages.  Drug Alcohol Depend. 2001;  62 149-54
• 21 Peterson P K, Gekker G, Lokensgard J R, Bidlack J M, Chang A C, Fang X, Portoghese P S. Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes.  Biochem Pharmacol. 2001;  61 1145-51
• 22 Chapuis A G, Rizzardi G P, D'Agostino C, Attinger A, Knabenhans C, Fleury S, Acha-Orbea H, Pantaleo G. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo .  Nat Med. 2000;  6 762-8