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Arzneimittelforschung 2005; 55(4): 223-231
DOI: 10.1055/s-0031-1296849
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

In vitro Anti-HIV Potency of Stampidine Alone and in Combination with Standard Anti-HIV Drugs

Fatih M. Uckun
a   Drug Discovery Program, Department of Virology, Parker Hughes Institute, St. Paul, MN, USA
b   Drug Discovery Program, Department of Chemistry, Parker Hughes Institute, St. Paul, MN, USA
c   Drug Discovery Program, Department of Bioinformatics, Parker Hughes Institute, St. Paul, MN, USA
d   Parker Hughes Center for Clinical Immunology, Roseville, MN, USA
e   Paradigm Pharmaceuticals, St. Paul, MN, USA
,
Sanjive Qazi
c   Drug Discovery Program, Department of Bioinformatics, Parker Hughes Institute, St. Paul, MN, USA
,
T. K. Venkatachalam
b   Drug Discovery Program, Department of Chemistry, Parker Hughes Institute, St. Paul, MN, USA
e   Paradigm Pharmaceuticals, St. Paul, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
23 December 2011 (online)

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Summary

The purpose of the present study was to compare the in vitro anti-HIV potency of stampidine (CAS 217178-62-6), a novel aryl phosphate derivative of stavudine (CAS 3056-17-5), and drug combinations containing stampidine to the anti-HIV potency of the standard drugs zidovudine (CAS 30516-87-1), stavudine, lamivudine (CAS 134678-17-4), nelfinavir (CAS 159989-65-8), and nevirapine (CAS 129618-40-2) as well as their combinations. Stampidine inhibited the laboratory HIV-1 strain HTLVIIIB (B-envelope subtype) as well as the primary clinical HIV-1 isolates BR/92/025 (C-envelope subtype) and BR/93/20 (F-envelope subtype) with subnanomolar IC50 values. Stampidine was as effective as zidovudine against HTLVIIIB and BR/92/025 and 3-logs more effective than zidovudine against BR/93/20. Stampidine was more effective than stavudine, lamivudine, nel-finavir, and nevirapine against all three HIV-1 isolates. The combination of stampidine with zidovudine + lamivudine was more effective than the combination of nelfinavir or nevirapine with zidovudine + lamivudine against all three HIV-1 isolates. The combination of stampidine with nelfinavir was more effective than zidovudine + lamivudine as well as the combination of zidovudine + lamivudine with nelfinavir. The combination of stampidine with lamivudine + nelfinavir was more effective than the combination of zidovudine with lamivudine + nelfinavir. The combination of stampidine with lamivudine + nevirapine was more effective than the combination of stavudine with lamivudine + nevirapine. These findings demonstrate that (a) stampidine, as well as its combinations with the standard anti-HIV drugs zidovudine, lamivudine, nelfinavir or nevirapine, are potent inhibitors of HIV-1 replication in human peripheral blood mononuclear cells, and (b) replacement of either zidovudine, zidovudine+lamivudine or stavudine in 3-drug cocktails with stampidine resulted in greater anti-HIV potency in vitro.

Zusammenfassung

Anti-HIV-Aktivität von Stampidin in vitro allein und in Kombination mit Anti-HIVStandardsubstanzen

Ziel dieser Studie war der Vergleich der Anti-HIV-Aktivität in vitro von Stampidin (CAS 217178-62-6), einem neuen Arylphosphat-Derivat von Stavudin (CAS 3056-17-5), und Stampidin-Kombinationen mit der Anti-HIV Aktivität der Standardsubstanzen Zidovudin (CAS 30516-87-1), Stavudin, Lamivudin (CAS 134678-17-4), Nelfinavir (CAS 159989-65-8) und Nevirapin (CAS 129618-40-2) sowie ihren Kombinationen. Stampidin hemmte sowohl den HIV-1-Laborstamm HTLVIIIB (B-envelope-Subtyp) als auch die primären klinischen HIV-1-Isolate BR/92/025 (C-envelope-Subtyp) und BR/93/20 (F-envelope-Subtyp) mit IC50-Werten im sub-nanomolaren Bereich. Stampidin war gegen HTLVIIIB und BR/92/025 gleich wirksam wie Zidovudin; gegen BR/93/20 war es wirksamer als Zidovudin. Stampidin zeigte gegen alle drei HIV-1-Isolate höhere Wirksamkeit als Stavudin, Lamivudin, Nelfinavir und Nevirapin. Die Kombination von Stampidin mit Zidovudin plus Lamivudin war wirksamer als die Kombination von Nelfinavir oder Nevirapin mit Zidovudin plus Lamivudin. Die Kombination von Stampidin mit Nelfinavir war wirksamer als Zidovudin plus Lamivudin mit oder ohne Nelfinavir. Die Kombination von Stampidin mit Lamivudin plus Nelfinavir war wirksamer als die Kombination Zidovudin plus Lamivudin plus Nelfinavir. Die Kombination von Stampidin mit Lamivudin plus Nevirapin war wirksamer als die Kombination von Stavudin mit Lamivudin plus Nevirapin. Die Ergebnisse zeigen, daß Stampidin und ihre Kombinationen mit anderen Anti-HIV-Substanzen die Replikation von HIV-1 in humanen Blutzellen verhindern. Stampidin konnte Zidovudin, Zidovudin plus Lamivudin und Stavudin ersetzen.

Key words

Anti-retroviral drugs - CAS 217178-62-6 - Stampidine, anti-HIV activity in vitro, drug combination, HIV isolates