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
| Autor: | L Field, Catherine A. Schaeffer, R J Schultz, S Terpening, D. J. Clanton, P K Singh, D C Baker, Jim A. Turpin, R W Buckheit, J P Bader, M Bu, L Graham, William G. Rice |
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| Rok vydání: | 1997 |
| Předmět: |
Anti-HIV Agents
HIV Core Protein p24 Gene Products gag Biology medicine.disease_cause Virus Replication gag Gene Products Human Immunodeficiency Virus Virus Cell Line Structure-Activity Relationship Viral Proteins Capsid medicine Structure–activity relationship Pharmacology (medical) Sulfones Pharmacology Zinc finger Drug discovery Zinc Fingers Simian immunodeficiency virus Zinc finger nuclease Virology Glutathione Infectious Diseases Biochemistry Viral replication HIV-1 Capsid Proteins Research Article |
| Zdroj: | Antimicrobial agents and chemotherapy. 41(2) |
| ISSN: | 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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