Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D. KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the allophenylnorstatine scaffold in the design of powerful and selective plasmepsin inhibitors.
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PMID:Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target. 1184 Dec 19

Drug development against viral or microbial targets is often compounded by the existence of naturally occurring polymorphisms or drug resistant mutations. In the case of Plasmodium falciparum, the etiological agent of malaria, four related and essential proteases, plasmepsin I, II, and IV and the histo-aspartyl protease (HAP), have been identified in the food vacuole of the parasite. Since all of these enzymes are involved in the hemoglobin degradation of infected victims, the simultaneous inhibition of the four enzymes can be expected to lead to a faster starvation of the parasite and to delay the onset of drug resistance, since four enzymes will need to mutate in a concerted fashion. This study describes the design of an adaptive inhibitor intended to inhibit the entire plasmepsin family. Adaptive inhibitors bind with extremely high affinity to a primary target within the family and maintain significant affinity against the remaining members. This objective is accomplished by engineering the strongest and most specific interactions of the inhibitor against conserved regions of the binding site and by accommodating target variations by means of flexible asymmetric functional groups. Using this approach, we have designed an inhibitor with subnanomolar affinity (0.5 nM) against the primary target, plasmepsin II, and with no loss or a very small loss of affinity against plasmepsin IV, I, and HAP (K(i) ratios of 0.4, 7.1, and 17.7, respectively). The core of the inhibitor is defined by an allophenylnorstatine scaffold. Adaptability is provided by an asymmetric amino indanol functional group facing one of the key variable regions in the binding site. Adaptive inhibitors, which display high affinity against several variations of a primary target, are expected to play an important role in the chemotherapy of infectious diseases.
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PMID:High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor. 1285 91