Substrate Cleavage by HIV-1 Proteinase

Abstract

The pol open reading frame (ORF) of the human immunodeficiency virus (HIV-1) encodes three distinct enzymes, one of which is an aspartic proteinase (PR). Point mutations introduced at the active site of this enzyme result in an inability to form infectious virions¹ thus emphasizing the paramount importance of PR in viral maturation. Proteinase has thus become a strategic target for the development of compounds that might have therapeutic value in the treatment of AIDS.² By preference, such compounds should be specific for the target, HIV-PR and should not have side effects by interacting with similar enzymes present in the human body, such as have been observed for example with anti-viral agents (e.g. AZT that act against reverse transcriptase RT). The design of specific PR inhibitors is facilitated considerably by a detailed understanding of the molecular topography of the PR active site. To this end, several series of synthetic chromogenic substrates have been used to unravel the subsite preferences of this important enzyme. In some cases, the requirement for certain residues to be present in particular locations in native protein substrates in order to ensure effective hydrolysis by PR has also been examined.