Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323

Erickson‐Viitanen, Susan; Klabe, Ronald M.; Cawood, P G; O'Neal, P L; Meek, James L.

doi:10.1128/aac.38.7.1628

Cited by 47 publications

(47 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibitors and K i Measurements-The inhibitors XK216, XK263, DMP323, DMP450, XV638, and SD146 were synthesized as reported (14, 19 -22), and their K i values were measured as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

DeLoskey

Huston

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

As long as the threat of human immunodeficiency virus (HIV) protease drug resistance still exists, there will be a need for more potent antiretroviral agents. We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit. The structures reveal that the preorganized, C 2 symmetric scaffolds of the inhibitors are anchored in the active site of the protease by six hydrogen bonds and that their P1 and P2 substituents participate in extensive van der Waals interactions and hydrogen bonds. Because all of our inhibitors possess benzyl groups at P1 and P1, their relative binding affinities are modulated by the extent of their P2 interactions, e.g. XK216, the least potent inhibitor (K i (inhibition constant) ‫؍‬ 4.70 nM), possesses the smallest P2 and the lowest number of P2-S2 interactions; whereas SD146, the most potent inhibitor (K i ‫؍‬ 0.02 nM), contains a benzimidazolylbenzamide at P2 and participates in fourteen hydrogen bonds and ϳ200 van der Waals interactions. This analysis identifies the strongest interactions between the protease and the inhibitors, suggests ways to improve potency by building into the S2 subsite, and reveals how conformational changes and unique features of the viral protease increase the binding affinity of HIV protease inhibitors.An essential step in the life cycle of the human immunodeficiency virus (HIV) 1 is the proteolytic cleavage of the viral polyprotein gene products of gag and gag-pol into active structural and replicative proteins (1, 2). The finding that a viralencoded protease is responsible for processing these precursors, and that its inactivation produces immature, noninfectious viral particles, elicited an intense search for synthetic inhibitors. The first competitive inhibitors of HIV protease (PR) were transition-state analogs (peptidomimetics) in which the scissile bonds were replaced with nonhydrolyzable isosteres such as a reduced amide, phosphinate, hydroxyethylene, dihydroxyethylene, statine, and hydroxyethylamine (3-5). Recently, the Food and Drug Administration (FDA) has approved the use of four peptidomimetic protease inhibitors (saquinavir, ritonavir, indinavir, and nelfinavir) to treat HIV infection. Although these compounds are potent inhibitors of the wild-type protease, their therapeutic benefit is, in most cases, short-lived because they select for variants of HIV that have a reduced sensitivity toward inhibitors, as a result of mutations within the HIV protease sequence (6 -10). In an attempt to delay the onset of drug resistance, the FDA approved the use of combination therapy, i.e. a mixture of protease and reverse transcriptase antiretroviral agents. Although multidrug therapy has reduced the plasma viral load of some HIV-infected individuals to undetectable levels (11), the daunting ability of the virus...

show abstract

Section: Methodsmentioning

confidence: 99%

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

DeLoskey

Huston

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Enzyme Assay-To measure the inhibitory potency of compounds, the discontinuous HPLC method described in Erickson-Viitanen et al (34) was used. The synthetic fluorescent cationic peptide substrate 2-aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr-Phe(NO 2 )-Val-Arg-Lys-Ala (28) was incubated with truncated or full-length HERV-K10 at 25°C in an assay buffer containing 50 mM MES, pH 5.0, 1 M NaCl, 20% glycerol, 1 mM EDTA.…”

Section: Methodsmentioning

confidence: 99%

“…Although cyclic ureas act as potent inhibitors of HIV-1 and HERV-K protease, they do not inhibit mammalian, nonretroviral cellular aspartic proteases (34). However, a question arises whether cell processes could be affected because of HERV-K protease inhibition.…”

mentioning

confidence: 99%

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites. To identify compounds that could inhibit protein processing dependent on the HERV-K10 protease, a series of cyclic ureas that had previously been shown to inhibit HIV-1 protease was tested. Several symmetric bisamides acted as very potent inhibitors of both the truncated and full-length form of HERV-K10 protease, in subnanomolar or nanomolar range, respectively. One of the cyclic ureas, SD146, can inhibit the processing of in vitro translated HERV-K10 Gag polyprotein substrate by HERV-K10 protease. In addition, in virus-like particles isolated from the teratocarcinoma cell line NCCIT, there is significant accumulation of Gag and Gag-Pol precursors upon treatment with SD146, suggesting the compound efficiently blocks HERV-K Gag processing in cells. This is the first report of an inhibitor able to block cell-associated processing of Gag polypeptides of an endogenous retrovirus.

show abstract

“…The ability of PIs to inhibit HIV type 1 (HIV-1) protease was assessed by using a fluorescent peptide substrate: aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr-Phe NO 2 -Val-ArgLys-Ala (the scissile bond is indicated in boldface) (8). Single-chain dimeric HIV protease was utilized to allow extremely low concentrations of the protease (50 pM) in reactions.…”

Section: Treatment Of N-[2r-hydroxy-3-[(2-methylpropyl)amino]-1s-(pmentioning

confidence: 99%

“…K i values were determined under conditions of substrate and inhibitor excess relative to the enzyme concentration (test compound concentration, 0.1 to 25 nM) by using the Michaelis-Menten equation for competitive inhibitors. Spectrophotometric and fluorometric assays were used to measure the inhibitory potency of DPC 681 and DPC 684 against cellular aspartyl proteases, chymotrypsin-like proteases, matrix metalloproteinases (MMPs), Factor X, and thrombin (8,31).…”

Section: Treatment Of N-[2r-hydroxy-3-[(2-methylpropyl)amino]-1s-(pmentioning

confidence: 99%

DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants

Kaltenbach

Trainor

Getman

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323

Cited by 47 publications

References 33 publications

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants

Contact Info

Product

Resources

About