Premium
Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases
Author(s) -
Nguyen JeffreyTri,
Hamada Yoshio,
Kimura Tooru,
Kiso Yoshiaki
Publication year - 2008
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200700267
Subject(s) - isostere , protease , peptidomimetic , chemistry , docking (animal) , protease inhibitor (pharmacology) , biochemistry , enzyme , biology , stereochemistry , medicine , virology , virus , peptide , nursing , antiretroviral therapy , viral load
In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two‐decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV‐1 protease, plasmepsins, β‐secretase, and HTLV‐I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T‐cell leukemia, HTLV‐I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate‐based drug design of peptidomimetics that potently inhibit the activity of renin, HIV‐1 protease, plasmepsins, β‐secretase, and HTLV‐I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non‐hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere‐containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non‐natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X‐ray crystallography, computer‐assisted docking and dynamic simulations, quantitative structure‐activity relationship studies, and various other methods that this review can barely mention.