Evaluation of the Physicochemical Properties of a Novel Antimalarial Drug Lead, Cyclen Bisquinoline

SummaryIsoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.

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Five Solid Forms of a Potent Imidazopyridazine Antimalarial Drug Lead: A Preformulation Study

Crystal Growth & Design ◽

10.1021/acs.cgd.9b00575 ◽

2019 ◽

Vol 19 (8) ◽

pp. 4683-4697 ◽

Cited By ~ 2

Author(s):

Terence J. Noonan ◽

Kelly Chibale ◽

Peter M. Cheuka ◽

Malkeet Kumar ◽

Susan A. Bourne ◽

...

Keyword(s):

Antimalarial Drug ◽

Drug Lead ◽

Preformulation Study

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Preparation and characterisation of vanadium pentoxide supported rhodium catalyst

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010010679x ◽

1988 ◽

Vol 46 ◽

pp. 946-947

Author(s):

A. Legrouri

Keyword(s):

Aqueous Solution ◽

Thermal Decomposition ◽

Physicochemical Properties ◽

Surface Area ◽

Vanadium Pentoxide ◽

High Purity ◽

Gas Adsorption ◽

Rhodium Catalyst ◽

Optical Methods ◽

Reducible Oxides

The industrial importance of metal catalysts supported on reducible oxides has stimulated considerable interest during the last few years. This presentation reports on the study of the physicochemical properties of metallic rhodium supported on vanadium pentoxide (Rh/V2O5). Electron optical methods, in conjunction with other techniques, were used to characterise the catalyst before its use in the hydrogenolysis of butane; a reaction for which Rh metal is known to be among the most active catalysts.V2O5 powder was prepared by thermal decomposition of high purity ammonium metavanadate in air at 400 °C for 2 hours. Previous studies of the microstructure of this compound, by HREM, SEM and gas adsorption, showed it to be non— porous with a very low surface area of 6m2/g3. The metal loading of the catalyst used was lwt%Rh on V2Q5. It was prepared by wet impregnating the support with an aqueous solution of RhCI3.3H2O.

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A rufomycin analogue is an anti-tuberculosis drug lead targeting CLPC1 with no cross resistance to ecumicin

Planta Medica ◽

10.1055/s-0035-1556165 ◽

2015 ◽

Vol 81 (11) ◽

Cited By ~ 5

Author(s):

M Choules ◽

Y Yu ◽

SH Cho ◽

J Anderson ◽

W Gao ◽

...

Keyword(s):

Cross Resistance ◽

Drug Lead

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Accelerating drug lead discovery from nature by high-resolution bioactivity profiling combined with HPLC-HRMS-SPE-NMR

Planta Medica ◽

10.1055/s-0036-1596170 ◽

2016 ◽

Vol 81 (S 01) ◽

pp. S1-S381

Author(s):

KT Kongstad ◽

NT Nyberg ◽

SG Wubshet ◽

D Staerk

Keyword(s):

High Resolution ◽

Lead Discovery ◽

Drug Lead

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Studies on the Degradation of Human Fibrinogen by Plasmin and Trypsin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655607 ◽

1966 ◽

Vol 16 (03/04) ◽

pp. 526-540 ◽

Cited By ~ 3

Author(s):

E. A Beck ◽

D. P Jackson

Keyword(s):

Physicochemical Properties ◽

Electrophoretic Mobility ◽

Rapid Loss ◽

Clotting System ◽

Human Fibrinogen ◽

Peptide Bonds ◽

Physico Chemical ◽

Starch Gel ◽

Ph Stat ◽

Rapid Appearance

SummaryThe effects of trypsin and plasmin on the functional and physicochemical properties of purified human fibrinogen were observed at various stages of proteolysis. Concentrations of plasmin and trypsin that produced fibrinogenolysis at comparable rates as measured in a pH stat produced, at similar rates, loss of precipitability of fibrinogen by heat and ammonium sulphate and alterations in electrophoretic mobility on starch gel. Trypsin produced a more rapid loss of clottability of fibrinogen and a more rapid appearance of inhibitors of the thrombin-fibrinogen clotting system than did plasmin. Consistent differences were noted between the effects of trypsin and plasmin on the immunoelectrophoretic properties of fibrinogen during the early stages of proteolysis.These results are consistent with the hypothesis that trypsin initially reacts with the same peptide bonds of fibrinogen that are split by thrombin, but these same bonds do not appear to be split initially by plasmin. Measurement of the various functional and physico-chemical changes produced by the action of trypsin and plasmin on fibrinogen can be used to recognize various stages of proteolysis.

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