HIV Life Cycle
Assembly of Virus
Assembly of infectious virions is dependent on the action of: (a) an aspartyl protease encoded by the viral pol gene and responsible for cleavage of the gag and gag-pol precursors into mature proteins (1,2) and (b) cellular N-protein myristoyl transferase (NMT) which adds myristic acid to the N-terminus of gag, gag-pol and nef viral polyprotein precursors(3). Research on the viral protease was facilitated by previous research on other aspartic proteases, including renin, inhibitors of which have potential as antihypertensive agents. As a result of cloning and purification of the HIV protease, development of rapid enzyme assays (4-10), and elucidation of enzyme structure, potent peptide-based inhibitors of HIV replication and selective for the HIV protease have been developed (11-17).
Potential problems with the use of peptide-based drugs include degradation by proteolytic enzymes and rapid elimination by the liver leading to a short duration of action, and poor bioavailability when taken orally. Chemical modifications to improve these properties is usually necessary.
A group at Abbott Laboratories initially exploited the C2 symmetry of the protease target to design a novel inhibitor with C2 symmetry (17,18). The lead compound was somewhat less peptide-like, containing two peptide N-termini but no C-terminus, and possessed activity against HIV in cell culture comparable to that observed with peptide analogs.
Specific inhibition of the myristoylation of HIV proteins by myristate analogs has also been pursued. Heteroatom substituted analogs of myristate were reported to inhibit HIV-1 replication in acutely infected CD4+ H9 cells at concentrations that were not toxic to uninfected cultured cells (19). Blockade of myristoylation was associated with a dramatic reduction in the rate of proteolytic processing of the polyprotein precursor by viral protease, probably resulting from an inability of the gag and gag-pol precursor to associate with the plasma membrane.
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- BRYANT, M.L.; HEUCKEROTH, R.O..; KIMATA, J.T.; RATNER, L.; AND GORDON, J.I. Replication of human immunodeficiency virus 1 and moloney murine leukemia virus is inhibited by different heteroatom-containing analogs of myristic acid. PROC NATL ACAD SCI USA, 86:8655-8659 (1989).