Journal article
Structure-activity relationships of biguanide-based compounds with activity against HIV-1
Journal of neurovirology, Vol.13, pp.111-111
01 Jan 2007
Abstract
Combination antiretroviral therapy, which is used as a highly effective treatment of HIV-1-associated immunopathogenesis, has also had a positive impact on neurologic disease caused by HIV-1 infection of the central nervous system (CNS). However, limits on treating or preventing HIV-1-associated neuropathogenesis due to reduced CNS drug penetration and drug-associated neurologic side effects underscore the importance of developing new drugs with greater efficacy within the CNS. In this regard, we have focused on the development of biguanide-based HIV-1 inhibitors. Our investigations, which demonstrated that biguanide-based compounds have activity against HIV 1, also suggested a relationship between biological activity and the lengths of hydrocarbon linkers surrounding the positively charged biguanide unit. To better define biguanide structure-activity relationships (SAR), biguanide oligomers with select linker lengths were evaluated for cytotoxicity, anti-HIV-1 activity, and in vivo toxicity. Results of the in vitro experiments demonstrated that (i) increases in linker length (and, therefore, increases in compound lipophilicity) were generally correlated with increases in cytotoxicity and antiviral activity against HIV-1, and (ii) polyethylene hexamethylene biguanide (PEHMB; biguanide units spaced between alternating ethylene and hexamethylene linkers) provided the greatest in vitro therapeutic indices (CC50/IC50) among the compounds tested. Additionally, the negligible toxicity of PEHMB relative to polyhexamethylene biguanide (PHMB; biguanide units alternating with hexamethylene linkers) in a murine model of cervicovaginal microbicide toxicity was consistent with considerable differences in cytotoxicity between PEHMB and PHMB observed during in vitro experiments. These SAR investigations represent an essential step in the development of biguanide-based inhibitors effective against HIV-1 CNS disease.
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Details
- Title
- Structure-activity relationships of biguanide-based compounds with activity against HIV-1
- Creators
- S PassicV PirroneB WigdahlT Kish-CataloneR RandoM LabibF Krebs
- Publication Details
- Journal of neurovirology, Vol.13, pp.111-111
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Identifiers
- 991019170611104721