Inhibition of Infection of T-Cells with Human Immunodeficiency Virus Type 1 by Dideoxynucleosides Conjugated with Oligopeptides

Abstract

We conjugated nucleoside derivatives that have anti-HIV-1 activities with oligopeptides that should bind to the gp120 of the HIV-1 virion, and examined their anti-HIV-1 activities. These derivates included 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyuridine (ddU), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyinosine (ddI) and 2′,3′-dideoxyadenine (ddA). Dipeptides consisting of N-carbomethoxy-carbonyl-prolyl-phenylalanylbenzyl ester (CPF) and oligopeptides derived from the complementarity-determining region 2 (CDR2) of domain 1 of CD4 were synthesized. The N-terminals of these peptides were conjugated with the 5′OH of AZT, ddU, ddC, ddl or ddA through carbonyl moieties. CPF conjugated with AZT, ddC, ddl or ddA through two-carbonyl moieties exhibited powerful anti-HIV-1 activity, which was similar to that of the respective nucleosides when compared at the same molar concentration. No complex compound connected by a one-carbonyl moiety had anti-HIV-1 activity, whereas a tetrapeptide or octapeptide of the CDR2 region combined with AZT did have such activity. The toxicity of these CPF-containing compounds to human peripheral blood lymphocytes was slightly weaker than the toxicities of the corresponding nucleosides lacking CPF. Antiviral nucleosides containing oligopeptides may be used as lead compounds in an effort to isolate more effective and less cytotoxic anti-HIV-1 agents.