A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity

Tj, Tucker; Wc, Lumma; Ls, Payne; Jm, Wai; Sj, de Solms; Ea, Giuliani; Pl, Darke; Jc, Heimbach; Ja, Zugay; Wa, Schleif

doi:10.1021/jm00092a002

Cited by 48 publications

(17 citation statements)

References 1 publication

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“…These lack a large aliphatic substituent group found in the statin-based drugs and contain a hydroxyethylamine core structure, which had previously been used as a transition-state mimic in the design of human immunodeficiency virus protease inhibitors (59). These compounds also contain a basic secondary amine, one prime side amino acid residue to minimize the size and peptidic nature of the inhibitor, and a large P1Ј substituent group (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors

Moura

Dame

Fidock

2009

Antimicrob Agents Chemother

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Hemoglobin (Hb) degradation is essential for the growth of the intraerythrocytic stages of malarial parasites. This process, which occurs inside an acidic digestive vacuole (DV), is thought to involve the action of four aspartic proteases, termed plasmepsins (PMs). These enzymes have received considerable attention as potential antimalarial drug targets. Leveraging the availability of a set of PM-knockout lines generated in Plasmodium falciparum, we report here that a wide range of previously characterized or novel aspartic protease inhibitors exert their antimalarial activities independently of their effect on the DV PMs. We also assayed compounds previously shown to inhibit cysteine proteases residing in the DV. The most striking observation was a ninefold increase in the potency of the calpain inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) against parasites lacking all four DV PMs. Genetic ablation of PM III or PM IV also decreased the level of parasite resistance to the ␤-hematin binding antimalarial chloroquine. On the basis of the findings of drug susceptibility and isobologram assays, as well as the findings of studies of the inhibition of Hb degradation, morphological analyses, and stage specificity, we conclude that the DV PMs and falcipain cysteine proteases act cooperatively in Hb hydrolysis. We also identify several aspartic protease inhibitors, designed to target DV PMs, which appear to act on alternative targets early in the intraerythrocytic life cycle. These include the potent diphenylurea compound GB-III-32, which was found to be fourfold less potent against a P. falciparum line overexpressing plasmepsin X than against the parental nontransformed parasite line. The identification of the mode of action of these inhibitors will be important for future antimalarial drug discovery efforts focusing on aspartic proteases.Plasmodium falciparum malaria continues to exert a tremendous burden on communities in tropical and subtropical regions of the world. Efforts to control this disease have been stymied by the acquisition of resistance by this parasite to key antimalarials, including chloroquine (CQ) and pyrimethaminesulfadoxine (60). Hemoglobin (Hb) degradation plays an essential role in malarial parasite development within infected red blood cells. As such, the parasite proteases involved in Hb degradation appear to be attractive targets for the development of novel antimalarials that are unaffected by the existing mechanisms of drug resistance.Hb digestion takes place in an acidic compartment, referred to as the digestive vacuole (DV; also known as the food vacuole) (23). This degradative process provides a source of amino acids and is thought to help maintain intracellular osmolarity during rapid parasite growth (40). Biochemical studies have implicated the DV aspartic proteases, termed plasmepsin (PMs), and the cysteine proteases, termed falcipains, as key mediators of this degradative process (24,51,55

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Section: Resultsmentioning

confidence: 99%

Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors

Moura

Dame

Fidock

2009

Antimicrob Agents Chemother

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“…A similar result with phenylglycinol as terminus was reported by Tucker et al . in the case of HIV PR inhibitors containing the hydroxyethylamine isostere …”

Section: Resultsmentioning

confidence: 99%

“…The combined organic layers were washed with brine and dried over MgSO 4 . The solvent was evaporated in vacuo to yield 37.7 g of 6 (92%): mp 115−117 °C; [α] 20 D = −38.0° (methanol, c = 1.11) (lit …”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Human Immunodeficiency Virus Type 1 Protease Containing 2-Aminobenzyl-Substituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Activity, and Oral Bioavailability

Lehr¹,

Billich

Charpiot

et al. 1996

J. Med. Chem.

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Systematic modifications of HIV protease inhibitor (2R,3S,4S)-4-[[(benzyloxycarbonyl)-L-valyl]-amino]-3-hydroxy-2-[(4- methoxybenzyl)amino]-5-phenylpentanoyl)-L-valine 2-(aminomethyl)- benzimidazole amide led to a novel series of inhibitors with shortened, modified carboxy terminus. Their synthesis, in vitro enzyme inhibitory data, and antiviral activities are reported. Of particular interest are derivatives featuring the (1S,2R)-1-amino-2-hydroxyindan moiety at the P2'-position since some of them exhibit substantial oral bioavailability in mice. The influence of aqueous solubility and structural parameters on the oral resorption of the inhibitors is discussed. Optimum enhancement of oral bioavailability was observed with L-tert-leucine in P2-position, resulting in the discovery of (2R,3S,4S)-4-[[(benzyloxycarbonyl)-L-tert-leucyl]- amino]-3-hydroxy-2-[(4-methoxybenzyl)amino]-5-phenylpentanoic acid (1S,2R)-1-amino-2-hydroxyindan amide which combines high antiviral activity (IC50 = 250 nM) with a good pharmacokinetic profile (AUC = 82.5 microM.h at a dose of 125 mg/kg po in mice).

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“…These type of compounds often display erratic oral bioavailability and are difficult to formulate as aqueous parenteral dosage forms. Generally, this problem is not encountered for linear peptides since most are innately hydrophilic and possess adequate aqueous solubility, although some new experimental HIV-protease inhibitors are quite insoluble (22,23). Many cyclic peptides are significantly less hydrophilic and possess lower aqueous solubility since the ionizable C-and N-terminus are capped upon cyclization.…”

Section: Improvement Of the Physicochemical Properties Of Polypeptidementioning

confidence: 99%

Prodrugs of Peptides and Proteins for Improved Formulation and Delivery

Oliyai¹,

Stella²

1993

Annu. Rev. Pharmacol. Toxicol.

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A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity

Cited by 48 publications

References 1 publication

Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors

Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors

Inhibitors of Human Immunodeficiency Virus Type 1 Protease Containing 2-Aminobenzyl-Substituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Activity, and Oral Bioavailability

Prodrugs of Peptides and Proteins for Improved Formulation and Delivery

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