In vivo antiviral activity of novel human immunodeficiency virus type 1 nucleocapsid p7 zinc finger inhibitors in a transgenic murine model.
Control of human immunodeficiency virus through the use of inexpensive chemotherapeutics, with minimal side effects and decreased potential for engendering resistant virus, is a long-term therapeutic goal. In principle, this goal can be accomplished if viral replication in reservoirs of chronically and latently infected cells is addressed. As a first step, we have developed novel antiviral compounds based on a 2-mercaptobenzamide thioester chemotype, including the pyridinioalkanoyl thioesters, which specifically target the zinc fingers of the human immunodeficiency virus nucleocapsid protein (NCp7). Using these compounds in a murine transgenic model, in which infectious human immunodeficiency virus is induced from an integrated provirus, we show inhibition of transgenic spleen cell p24 expression with potencies comparable to acute infection assays using human peripheral blood lymphocytes. More importantly, transgenic mice treated in vivo with two 2-mercaptobenzamide thioesters expressed significantly lower plasma p24, and splenocytes from these animals produced fewer infectious virions. Thus, these thioesters may provide an effective means for inhibiting the expression of human immunodeficiency virus from integrated viral reservoirs.
Schito
Marco L
ML
Chemical Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA. schitom@mail.nih.gov
Goel
Atul
A
Song
Yongsheng
Y
Inman
John K
JK
Fattah
Rasem J
RJ
Rice
William G
WG
Turpin
Jim A
JA
Sher
Alan
A
Appella
Ettore
E
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000737:chemistry; D036022:Capsid Proteins; D004195:Disease Models, Animal; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D015683:Gene Products, gag / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014764:Viral Proteins; D016335:Zinc Fingers / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D001549:Benzamides; D036022:Capsid Proteins; D004952:Esters; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D011726:Pyridinium Compounds; D013438:Sulfhydryl Compounds; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus