Plasmepsins (PLMs) are a family of plasmodial aspartic proteases involved in the degradation of haemoglobin by the erythrocytic stage of the parasite. Several potent inhibitors have been designed, by replacement of the scissile peptide bond with a transition state analogue, but effectiveness in killing the parasite was limited (IC50 range 1‐20 μM). The low potency against cultured parasites may be explained by the PLMs redundancy which implies that blockage of this enzyme family may not be lethal. [A. L. Omara‐Opyene, et al, J. Biol. Chem. 2004, 279, 54088.; J. Liu, et al Proc Natl Acad Sci U S A 2006, 103, 8840] We developed new antimalarial agents designed according to the double‐drug approach. Statine, responsible for PLMs inhibition, has been bound through an aromatic linker to a known antimalarial drug (Primaquine, Atovaquone), consequently allowing to overcome the problems associated with poor pharmacokinetics of peptido‐mimetics and improve antimalarial activity[M. Dell'Agli, et al J. Med. Chem. 2006, 49, 7440]. We report here the synthesis, the inhibition of PLM2 and PLM4 and the antiplasmodial activities of new double drugs designed by joining statine, a plasmepsins inhibitor, with the 7‐chloro‐4‐ aminoquinoline ring system derived from chloroquine (CQ). All compounds inhibited PLM2 and PLM4 in a nanomolar range (Ki 0.5‐20 nM). Antiplasmodial activities were as low as 64 nM (IC50, W2 CQ‐resistant strain): an excellent improvement over CQ (IC50: 870 nM, W2 CQ‐resistant strain). The most promising compounds were not cytotoxic against human fibroblasts at 100 μM and were highly selective for PLMs vs human cathepsin D. CQ is supposed to act against Pf by inhibiting the detoxification of haem released during haemoglobin digestion by PLMs, therefore the inhibition of PLMs could antagonize the effects of CQ. CQ‐statine double drugs have been synthesized considering that, although PLMs are efficaciously inhibited by statine, there could be a continuous release of haem by the action of other proteolytic enzymes present in the digestive vacuole. The remarkable activities of the CQstatine double drugs against the W2 CQ‐R strain seem to confirm this hypothesis.

4-Aminoquinoline-statine double drugs / S. Romeo, N. Vaiana, M. Marzahn, S. Parapini, P. Liu, M. Dell'Agli, A. Pancotti, L. Rizzi, E. Sangiovanni, S. D'Alessandro, E. Bosisio, B.M. Dunn, D. Taramelli. ((Intervento presentato al convegno Antimal - Antimalarial Drugs : chemistry, development and future challenges tenutosi a London nel 2011.

4-Aminoquinoline-statine double drugs

S. Romeo;N. Vaiana;S. Parapini;M. Dell'Agli;A. Pancotti;L. Rizzi;E. Sangiovanni;S. D'Alessandro;E. Bosisio;D. Taramelli
2011-03-15

Abstract

Plasmepsins (PLMs) are a family of plasmodial aspartic proteases involved in the degradation of haemoglobin by the erythrocytic stage of the parasite. Several potent inhibitors have been designed, by replacement of the scissile peptide bond with a transition state analogue, but effectiveness in killing the parasite was limited (IC50 range 1‐20 μM). The low potency against cultured parasites may be explained by the PLMs redundancy which implies that blockage of this enzyme family may not be lethal. [A. L. Omara‐Opyene, et al, J. Biol. Chem. 2004, 279, 54088.; J. Liu, et al Proc Natl Acad Sci U S A 2006, 103, 8840] We developed new antimalarial agents designed according to the double‐drug approach. Statine, responsible for PLMs inhibition, has been bound through an aromatic linker to a known antimalarial drug (Primaquine, Atovaquone), consequently allowing to overcome the problems associated with poor pharmacokinetics of peptido‐mimetics and improve antimalarial activity[M. Dell'Agli, et al J. Med. Chem. 2006, 49, 7440]. We report here the synthesis, the inhibition of PLM2 and PLM4 and the antiplasmodial activities of new double drugs designed by joining statine, a plasmepsins inhibitor, with the 7‐chloro‐4‐ aminoquinoline ring system derived from chloroquine (CQ). All compounds inhibited PLM2 and PLM4 in a nanomolar range (Ki 0.5‐20 nM). Antiplasmodial activities were as low as 64 nM (IC50, W2 CQ‐resistant strain): an excellent improvement over CQ (IC50: 870 nM, W2 CQ‐resistant strain). The most promising compounds were not cytotoxic against human fibroblasts at 100 μM and were highly selective for PLMs vs human cathepsin D. CQ is supposed to act against Pf by inhibiting the detoxification of haem released during haemoglobin digestion by PLMs, therefore the inhibition of PLMs could antagonize the effects of CQ. CQ‐statine double drugs have been synthesized considering that, although PLMs are efficaciously inhibited by statine, there could be a continuous release of haem by the action of other proteolytic enzymes present in the digestive vacuole. The remarkable activities of the CQstatine double drugs against the W2 CQ‐R strain seem to confirm this hypothesis.
4-aminoquinoline-statine ; plasmepsins ; malaria
Settore CHIM/08 - Chimica Farmaceutica
Settore MED/04 - Patologia Generale
Settore BIO/15 - Biologia Farmaceutica
Liverpool School of Tropical Medicine
http://www.antimal.eu/conference/documents/ConferenceAbstractBook.pdf
4-Aminoquinoline-statine double drugs / S. Romeo, N. Vaiana, M. Marzahn, S. Parapini, P. Liu, M. Dell'Agli, A. Pancotti, L. Rizzi, E. Sangiovanni, S. D'Alessandro, E. Bosisio, B.M. Dunn, D. Taramelli. ((Intervento presentato al convegno Antimal - Antimalarial Drugs : chemistry, development and future challenges tenutosi a London nel 2011.
Conference Object
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/155807
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact