Inhibition of multiple phases of human immunodeficiency virus type 1 replication by a dithiane compound that attacks the conserved zinc fingers of retroviral nucleocapsid proteins

Abstract

The human immunodeficiency virus type 1 (HIV-1) nucleocapsid p7 protein contains two retrovirus-type zinc finger domains that are required for multiple phases of viral replication. Chelating residues (three Cys residues and one His residue) of the domains are absolutely conserved among all strains of HIV-1 and other retroviruses, and mutations in these residues in noninfectious virions. These properties establish the zinc finger domains as logical targets for antiviral chemotherapy. Selected dithiobis benzamide (R-SS-R) compounds were previously found to inhibit HIV-1 replication by mediating an electrophilic attack on the zinc fingers. Unfortunately, reaction of these disulfide-based benzamides with reducing agents yields two monomeric structures (two R-SH structures) that can dissociated and no longer react with the zinc fingers, suggesting that in vivo reduction would inactivate the compounds. Through an extensive drug discovery program of the National Cancer Institute, a nondissociable tethered dithiane compound (1,2-dithiane-4,5-diol, 1,1-dioxide, cis; NSC 624151) has been identified. This compound specifically attacks the retroviral zinc fingers, but not other antiviral targets. The lead compound demonstrated broad antiretroviral activity, ranging from field isolates and drug-resistant strains of HIV-1 to HIV-2 and simian immunodeficiency virus. The compound directly inactivated HIV-1 virions and blocked production of infectious virus from cells harboring integrated proviral DNA. NSC 624151 provides a scaffold from which medicinal chemists can develop novel compounds for the therapeutic treatment of HIV infection.

Advances in targeting nucleocapsid–nucleic acid interactions in HIV-1 therapy

“…Because of the critical role of the cysteines in the zinc fingers, covalent binding zinc ejectors are not susceptible to the development of resistance (Jenkins et al, 2010). Various categories of compounds in this class were reported during the 1990s, including 3-nitrosobenzamide (NOBA) (Rice et al, 1993), 2,2’-dithiobisbenzamide (DIBA) (Rice et al, 1995), cyclic 2,2’- dithiobisbenzamide (Witvrouw et al, 1997), 1,2-dithiane-4,5-diol-1,1-dioxide (Rice et al, 1997a), azadicarbonamide (ADA) (Rice et al, 1997b) and pyridinioalkanoyl 2-mercaptobenzamide thioesters (PATE) (Turpin et al, 1999). The structure and activity of these zinc ejectors has been reviewed by Rocquigny et al (de Rocquigny et al, 2008).…”

Novel targets for anti-retroviral therapy

“…54 Another compound, NSC 624151 was found to be active against wild type and drug resistant HIV-1 and HIV-2 viruses. 55 A third compound e Azodicarbonamide, when introduced in phase I and II trials in Europe for advanced AIDS, showed dose dependent side effects (nephrolithiasis, glucose intolerance, CD4 cytotoxicity). 56 The side effects are not unsurprising as zinc fingers are not unique targets or used by HIV alone and are found in mammalian cells.…”

Targeting Human Immunodeficiency Virus Type 1 Assembly, Maturation and Budding

“…The non-dissociable tethered dithiane compound 1,2-dithiane-4,5-diol,1,1-dioxide, (NSC 624151) also mediates similar defects in Gag processing (Rice et al 1997). Although cellular proteins also contain zinc fingers, these inhibitors appear to preferentially target retro-viral zinc fingers.…”