Abstract
HIV/AIDS has been one of the most devastating global diseases. HIV-1 protease proteolytic action is responsible for the manufacture of grown, infectious species, consequently HIV-1 protease has become an attractive goal in the treatment and therapy of HIV. Several HIV-1 protease inhibitors based therapeutic agents are under investigation or currently in the market. Lopinavir (ABT-378) has a great value in this research field. Therefore, different methods have appeared aiming to develop efficient analogs by the utilization of variable techniques, since Lopinavir had showed low bioavailability when being prescribed alone, and various side effects after the combination of Lopinavir with another HIV-1 inhibitors such as Ritonavir, which is available in the markets nowadays under the brand name Kaletra. Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and consequently supports the drug affinity to the protease. The small scale processes for the synthetic strategies for the new candidate phosphinic analog of Lopinavir protease inhibitor (PL1) is presented here in along with some preliminary pharmacological data.
Highlights
Replacement of the hydroxyethylene moiety in Lopinavir structure, which is responsible for the monohydroxylated metabolites with the stable to hydrolysis phosphinic group has been considered, since that hydroxyl group in the central core is responsible for the interaction with the carboxylic acid in the catalytic aspartyl residue of HIV-1 by hydrogen bonding and supports the drug affinity to the protease
HIV-1 protease is classified as an aspartic acid protease which contains 99 amino acid residues that include the active site at the interface between the protein units with a homodimer function, and similar to all dimers, it is symmetrical, with two fold rotational (C2) symmetry [2]
It has the ability to prevent the transformation process of polyprotein precursors into the mature form, and as a result, it blocks the division and replication operation of the protease inside the virus. It was discovered in 2000 as an improved analog of Ritonavir, and was firstly prescribed to control the interactions between Val 82 active site residues of the HIV-1 protease with the inhibitor, the residuals of the virus were considerably transformed into drug resistant strains [3]
Summary
It has the ability to prevent the transformation process of polyprotein precursors into the mature form, and as a result, it blocks the division and replication operation of the protease inside the virus. It was discovered in 2000 as an improved analog of Ritonavir, and was firstly prescribed to control the interactions between Val 82 active site residues of the HIV-1 protease with the inhibitor, the residuals of the virus were considerably transformed into drug resistant strains [3]. Phosphinic peptide inhibitors of aspartic acid proteases have been reported for serine proteases [7] and serine kinases [8]
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