Binding of a Reduced-Peptide Inhibitor and a Statine-Containing Inhibitor to the Protease from the Human Immunodeficiency Virus

Abstract

In the replication cycle of human immunodeficiency virus, viral mRNA is translated as a polyprotein precursor. Cleavage by a viral-encoded protease is required for release of mature viral structural proteins and enzymes from the precursor; the key role of the protease in the maturation of this virus, the causative agent in acquired immune deficiency syndrome (AIDS), makes the it an attractive target for therapeutic intervention in the treatment of AIDS. To aid in the design of safe and effective inhibitors, we have studied the structure of the protease from human immunodeficiency virus type 1 (HIV-1), both in its native state¹ and in complex with a statine-containing inhibitor, acetyl-pepstatin². We report here the determination of the structure of the protease in complex with a reduced-peptide inhibitor, L365,862 (Ser-Gln-Asn-PheΨ(CH2-N)Pro-Ile-Val-Gln). The amino acid sequence of this peptide corresponds to the cleavage site between the membrane-associated and capsid proteins in the polyprotein (with the substitution of Phe for Tyr); the replacement of the scissile bond in this octapeptide with a reduced-peptide linkage generates an inhibitor that has been used as an affinity ligand in the purification of the protease³. Although the structure of this complex is still being refined, a preliminary comparison to the structure of the complex between HIV-1 protease and acetyl-pepstatin reveals considerable difference in the length of hydrogen bonds between the protein and the inhibitor. The conformation of the backbone of most of the inhibitor is extended, but the backbone has a turn conformation at the position of the amino-terminal serine residue; turn-forming at this position may facilitate binding between the protease and its natural substrates.