Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases Plasmepsin I and II. Use of Solid-Phase Synthesis to Explore Novel Statine Motifs

Johansson, Per-Ola; Chen, Yantao; Belfrage, Anna Karin; Blackman, Michael J.; Kvarnström, Ingemar; Jansson, Krister N.; Vrang, Lotta; Hamelink, Elizabeth; Hallberg, Anders; Rosenquist, Åsa; Samuelsson, Bertil

doi:10.1021/jm031106i

Cited by 50 publications

(71 citation statements)

References 39 publications

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“…In our laboratories we have synthesized a series of statine-based inhibitors with extended P1 side chains, essentially starting from the previously reported inhibitor 9 (e.g., inhibitor 10-12, Table I). 131 The elongated P1 side chain was predicted to be accommodated in the continuous S1-S3 pocket. Inhibitor 11 with a p-bromobenzyloxy in P1 was the most potent plasmepsin inhibitor in this series.…”

Section: Statinesmentioning

confidence: 99%

Plasmepsins as potential targets for new antimalarial therapy

2006

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Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum-infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared.

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Section: Statinesmentioning

confidence: 99%

Plasmepsins as potential targets for new antimalarial therapy

2006

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“…A family of P. falciparum aspartic proteases called plasmepsins has been found to be important for the initiation of hemoglobin degradation in vitro and in vivo (3,4), and considerable effort is being spent in developing potent plasmepsin inhibitors (5)(6)(7)(8)(9). Plasmepsin II (PM II), 1 for which the recombinant enzyme can be expressed readily and the crystal structure is available, has been the primary focus of drug design efforts.…”

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The Role of Plasmodium falciparum Food Vacuole Plasmepsins

Gluzman

Drew

et al. 2005

Journal of Biological Chemistry

194

167

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Plasmepsins (PMs) are thought to have an important function in hemoglobin degradation in the malarial parasite Plasmodium falciparum and have generated interest as antimalarial drug targets. Four paralogous plasmepsins reside in the food vacuole of P. falciparum. Targeted gene disruption by double crossover homologous recombination has been employed to study food vacuole plasmepsin function in cultured parasites. Parasite clones with deletions in each of the individual PM I, PM II, and HAP genes as well as clones with a double PM IV/PM I disruption have been generated. All of these clones lack the corresponding PMs, are viable, and appear morphologically normal. PM II and PM IV/I disruptions have longer doubling times than the 3D7 parental line in rich RPMI medium. This appears to be because of a decreased level of productive progeny rather than an increased cell cycle time. In amino acid-limited medium, all four knockouts exhibit slower growth than the parental strain. Compared with 3D7, knock-out clone sensitivity to aspartic and cysteine protease inhibitors is changed minimally. These results suggest substantial functional redundancy and have important implications for the design of antimalarial drugs. The slow growth phenotype may explain why P. falciparum has maintained four plasmepsin genes with overlapping functions.

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“…Like these HIV-1 aspartyl protease inhibitors, most Plm I and II inhibitors mimic the tetrahedral intermediate formed during the aspartyl protease catalysis. There are several transition state analogue cores used for the design of Plm inhibitors [35,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65], but the most important include the statine core [54,56,57,64], the reversed-statine core [53,54], or a hydroxyethylamine motif (Fig. 4) [56,61,62].…”

Section: Aspartyl Proteases (Plasmepsins)mentioning

confidence: 99%

“…(4). Transition-state mimicking groups in peptidomimetic plasmepsin inhibitors: reduced amine [52,59], statine [54,56,57,64], hydroxypropylamine [51], reversed-statine [53,54], dihydroxyethylene (C-and N-duplicated) [35,55,63], norstatine [58,60,65], and hydroxyethylamine [56,61,62].…”

Section: Aspartyl Proteases (Plasmepsins)mentioning

confidence: 99%

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

Pérez

Teixeira

Gomes³

et al. 2013

CMC

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New drug targets for the development of antimalarial drugs have emerged after the unveiling of the Plasmodium falciparum genome in 2002. Potential antimalarial drug targets can be broadly classified into three categories according to their function in the parasite's life cycle: (i) biosynthesis, (ii) membrane transport and signaling, and (iii) hemoglobin catabolism. The latter plays a key role, as inhibition of hemoglobin degradation impairs maturation of bloodstage malaria parasites, ultimately leading to remission or even cure of the most severe stage of the infection. Intraerythrocytic Plasmodia parasites have limited capacity to biosynthesize amino acids which are vital for their growth. Therefore, the parasites obtain those essential amino acids via degradation of host cell hemoglobin, making this a crucial process for parasite survival. Several plasmodial proteases are involved in hemoglobin catabolism, among which plasmepsins and falcipains are well-known examples. Hence, development of P. falciparum protease inhibitors is a promising approach to antimalarial chemotherapy, as highlighted by the present review which is focused on the Medicinal Chemistry research effort recorded in the past decade in this particular field.

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Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases Plasmepsin I and II. Use of Solid-Phase Synthesis to Explore Novel Statine Motifs

Cited by 50 publications

References 39 publications

Plasmepsins as potential targets for new antimalarial therapy

Plasmepsins as potential targets for new antimalarial therapy

The Role of Plasmodium falciparum Food Vacuole Plasmepsins

Development of Plasmodium falciparum Protease Inhibitors in the Past Decade (2002–2012)

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