Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D

Carroll, Carolyn DiIanni; Johnson, Theodore; Tao, Shewei; Lauri, Giorgio; Orlowski, Marc; Gluzman, Ilya Y.; Goldberg, Daniel E.; Dolle, Roland E.

doi:10.1016/s0960-894x(98)00554-x

Cited by 54 publications

(39 citation statements)

References 6 publications

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“…A direct correlation between the compounds' activity against Plm II and the in vitro parasite growth suggested that the main mechanism of these inhibitors was Plm II inhibition and consequently, the digestion of hemoglobin that is essential for Pf survival as stated before. Compound with the linker derived from a succinic acid was the least active of the series which is in agreement with the finding suggesting that an aromatic substituent is preferred in P3 for Plm II inhibition [66]. The introduction of an aromatic ring as a linker in general structure 6 increased the activity as expected and compounds with a naphthyl were more active against Plm II.…”

Section: Aspartyl Proteases (Plasmepsins)supporting

confidence: 90%

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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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Section: Aspartyl Proteases (Plasmepsins)supporting

confidence: 90%

“…In addition, P2 and P3 substituents impart selectivity in Plm II inhibitors (Fig. 5) [66,67]. One advantage of this type of inhibitors is that they don't cross inhibit other proteases such as serine-, cysteine-, or metallo-proteases [68].…”

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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“…This compound, which also blocked the majority of hemoglobin digestion in DV preparations, was reported to be more efficient in inhibiting PfPM1 than PfPM2 (5). Based on these observations, several projects have been undertaken to identify specific inhibitors for PfPM1 and PfPM2 (41)(42)(43)(44)(45)(46). A search for inhibitors has also been performed with the Plasmodium vivax DV plasmepsin, PvPM4, for which active recombinant protein was available (47).…”

Section: Discussionmentioning

confidence: 99%

“…Some evidence for this being the case comes from structural studies that reveal close active site similarity between PfPM2 and the P. vivax ortholog of PfPM4 (54, 56 -58). 3 Most importantly, these DV plasmepsins differ sufficiently from the most closely related human aspartic proteinase, cathepsin D (59), making it potentially feasible to develop selective anti-plasmodial inhibitors (41,44). Indeed, the practicality of a strategy to design inhibitors capable of inhibiting the whole family of DV plasmepsins has been reported recently (55).…”

Section: Discussionmentioning

confidence: 99%

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

Omara-Opyene

Moura

Sulsona

et al. 2004

Journal of Biological Chemistry

128

103

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The digestive vacuole plasmepsins PfPM1, PfPM2, PfPM4, and PfHAP (a histoaspartic proteinase) are 4 aspartic proteinases among 10 encoded in the Plasmodium falciparum malarial genome. These have been hypothesized to initiate and contribute significantly to hemoglobin degradation, a catabolic function essential to the survival of this intraerythrocytic parasite. Because of their perceived significance, these plasmepsins have been proposed as potential targets for antimalarial drug development. To test their essentiality, knockout constructs were prepared for each corresponding gene such that homologous recombination would result in two partial, nonfunctional gene copies. Disruption of each gene was achieved, as confirmed by PCR, Southern, and Northern blot analyses. Western and two-dimensional gel analyses revealed the absence of mature or even truncated plasmepsins corresponding to the disrupted gene. Reduced growth rates were observed with PfPM1 and PfPM4 knockouts, indicating that although these plasmepsins are not essential, they are important for parasite development. Abnormal mitochondrial morphology also appeared to accompany loss of PfPM2, and an abundant accumulation of electron-dense vesicles in the digestive vacuole was observed upon disruption of PfPM4; however, those phenotypes only manifested in about a third of the disrupted cells. The ability to compensate for loss of individual plasmepsin function may be explained by close similarity in the structure and active site of these four vacuolar enzymes. Our data imply that drug discovery efforts focused on vacuolar plasmepsins must incorporate measures to develop compounds that can inhibit two or more of this enzyme family.

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“…[2] Various methods for the preparation of optically active a,b-diamino derivatives have been established. [3] Most of these approaches have focused on Mannich reactions of glycine imines or nitro esters with various imines, which provide a direct and favorable method for the construction of these compounds.…”

mentioning

confidence: 99%

Guanidine Organocatalyst for the Asymmetric Mannich‐Type Reaction between α‐Isothiocyanato Imide and Sulfonyl Imines

Chen

Dong

Qiao

et al. 2011

Chemistry A European J

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Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D

Cited by 54 publications

References 6 publications

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

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

Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy

Guanidine Organocatalyst for the Asymmetric Mannich‐Type Reaction between α‐Isothiocyanato Imide and Sulfonyl Imines

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