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PDBsum entry 4zx5
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Hydrolase/hydrolase inhibitor
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PDB id
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4zx5
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References listed in PDB file
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Key reference
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Title
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Potent dual inhibitors of plasmodium falciparum m1 and m17 aminopeptidases through optimization of s1 pocket interactions.
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Authors
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N.Drinkwater,
N.B.Vinh,
S.N.Mistry,
R.S.Bamert,
C.Ruggeri,
J.P.Holleran,
S.Loganathan,
A.Paiardini,
S.A.Charman,
A.K.Powell,
V.M.Avery,
S.Mcgowan,
P.J.Scammells.
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Ref.
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Eur J Med Chem, 2016,
110,
43-64.
[DOI no: ]
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PubMed id
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Abstract
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Malaria remains a global health problem, and though international efforts for
treatment and eradication have made some headway, the emergence of
drug-resistant parasites threatens this progress. Antimalarial therapeutics
acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and
M17 are neutral aminopeptidases which are essential for parasite growth and
development. Previous work in our group has identified inhibitors capable of
dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the
protease S1 pockets that could be exploited in the development of ligands with
improved inhibitory activity. Herein, we report the structure-based design and
synthesis of novel hydroxamic acid analogues that are capable of potent
inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds
potently inhibit Pf growth in culture, including the multi-drug resistant strain
Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be
an attractive strategy for the design of novel antimalarial therapeutics.
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