Structure−Activity Relationship of Small-Sized HIV Protease Inhibitors Containing Allophenylnorstatine

Mimoto, Tsutomu; Kato, Ryohei; Takaku, Haruo; Nojima, Satoshi; Terashima, Keisuke; Misawa, S.; Fukazawa, Tominaga; Ueno, Takamasa; Sato, Hideharu; Shintani, Makoto; Kiso, Yoshiaki; Hayashi, Hideya

doi:10.1021/jm980637h

Cited by 73 publications

(66 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…JE-533 and JE-2147, both of which are dipeptidic compounds containing allophenylnorstatine (Fig. 1), were designed and synthesized as described elsewhere (8). The properties of KNI-272 also containing allophenylnorstatine are described elsewhere (9).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

Yoshimura

Kato

Yusa

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

113

153

View full text Add to dashboard Cite

We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC 50 values ranging from

show abstract

Section: Methodsmentioning

confidence: 99%

“…We designed and synthesized JE-2147 and its related compounds, which represent a class of transition-state mimetic dipeptide HIV protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [(2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as an active moiety (8) (Fig. 1).…”

mentioning

confidence: 99%

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

Yoshimura

Kato

Yusa

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

113

153

View full text Add to dashboard Cite

show abstract

“…Kynostatin-227 (also known as KNI-227, 11) with a P19 L-5,5-dimethylthiazolidine-4-carboxylic acid moiety seemed to exhibit a slight improvement in inhibitory activity against HIV-1 protease, possibly due to the conformational constraint and hydrophobicity of the bulky dimethyl group. Both inhibitors KNI-272 and KNI-227 were superpotent and highly selective HIV-1 protease inhibitors (IC 50 , K i ) with excellent antiviral activity in cells (EC 50 ) [22,23]. Particularly, KNI-272 also had high antiviral activity against a wide spectrum of HIV strains and a low cytotoxicity profile against non-infected cells (LC 50 A 20 lM).…”

Section: Hiv Protease Inhibitorsmentioning

confidence: 99%

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

Nguyen

Hamada

Kimura

et al. 2008

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

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, b-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, b-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.

show abstract

“…The significantly reduced activity of the α-picolinyl derivative 7i may be attributed to the possible competition for intramolecular hydrogen bond formation between the pyridine N and the amidic NH, which participates in a crucial hydrogen bonding with the water molecule bridging Ala28 and Asp29 in the S 2 Ј site of the enzyme [15]. In the absence of such interaction, higher activity of the β-and γ-picoline 7g and 7h was observed.…”

Section: Structure Activity Relationship Against Hiv-1 Proteasementioning

confidence: 99%

A Novel Dipeptide‐based HIV Protease Inhibitor Containing Allophenylnorstatine

Abdel‐Rahman

El-Koussi

Alkaramany

et al. 2004

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Dipeptide analogues incorporating allophenylnorstatine [Apns; (2S,3S)-3amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic at the scissile bond were designed and synthesized in the hope of obtaining a novel KNI series of HIV protease inhibitors. The precursors, N-P2'-3-(2S,3S)-3-(tert-butyloxy-carbonyl)amino-2-hydroxy-4-phenylbutanoyl)-5,5-dimethylthiazolidine-4-carboxamide (N-Boc-Apns-Dmt-P2') 4a-p were prepared by deprotection of the synthones N-P2'-(tert-butyloxycarbonyl)-5,5-dimethylthiazolidine-4-carboxamide (Boc-Dmt-P2') 2a-p, then coupling with (2S,3S)3-(tert-butyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoic acid (N-Boc-Apns-OH) 3. The deprotected intermediates 4 were coupled with the activated carboxyl groups of the P2 ligands to afford the target dipeptides. In this work, we fixed at the P2 site either a 2,6-dimethylphenoxyacetyl or a 3-hydroxy-2-methylbenzoyl group. Substitutes at the P2' site were varied to afford the members of the series 7 and 8. Improved activity of most of the members of series 8 relative to their analogues of series 7 can be partially attributed to the differences in the structures of the P2 moieties. Positional isomerism in the P2' moieties significantly affected the activity and polarity of the target.

show abstract

Structure−Activity Relationship of Small-Sized HIV Protease Inhibitors Containing Allophenylnorstatine

Cited by 73 publications

References 26 publications

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases

A Novel Dipeptide‐based HIV Protease Inhibitor Containing Allophenylnorstatine

Contact Info

Product

Resources

About