Hemeproteins

Publication Title: 
The Journal of Biological Chemistry

Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin.

Author(s): 
Pandey, A. V.
Tekwani, B. L.
Singh, R. L.
Chauhan, V. S.
Publication Title: 
The Biochemical Journal

Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem.

Author(s): 
Kannan, Rangiah
Kumar, Krishan
Sahal, Dinkar
Kukreti, Shrikant
Chauhan, Virander S.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Trioxaquines, potential antimalarial agents, and heme-artemisinin adducts, resulting from the alkylation of heme by artemisinin, were evaluated as inhibitors of beta-hematin formation in 10 M acetate medium at pH 5.

Author(s): 
Loup, Christophe
Lelièvre, Joel
Benoit-Vical, Françoise
Meunier, Bernard
Publication Title: 
Antimicrobial Agents and Chemotherapy

In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn(2+) complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities.

Author(s): 
Khan, M. O. Faruk
Levi, Mark S.
Tekwani, Babu L.
Khan, Shabana I.
Kimura, Eiichi
Borne, Ronald F.
Publication Title: 
Combinatorial Chemistry & High Throughput Screening

The growing drug resistance of Plasmodia spp. to current antimalarial agents in the quinine and artemisinin families further asserts the need for novel drug classes to combat malaria infection. One approach to the discovery of new antimalarials is the screening of natural product extracts for activity against the formation of hemozoin, a biomineral essential to parasite survival. By mimicking the in vivo lipid-water interface at which native hemozoin is found, hemozoin can be synthesized outside the parasite.

Author(s): 
Carter, Melissa D.
Phelan, Vanessa V.
Sandlin, Rebecca D.
Bachmann, Brian O.
Wright, David W.
Publication Title: 
Bioorganic & Medicinal Chemistry

In continuing our search of potent antimalarials based on 8-aminoquinoline structural framework, three series of novel bis(8-aminoquinolines) using convenient one to four steps synthetic procedures were synthesized. The bisquinolines were evaluated for in vitro antimalarial (Plasmodiumfalciparum), antileishmanial (Leishmaniadonovani), antimicrobial (a panel of pathogenic bacteria and fungi), cytotoxicity, ?-hematin inhibitory and methemoglobin (MetHb) formation activities. Several compounds exhibited superior antimalarial activities compared to parent drug primaquine.

Author(s): 
Kaur, Kirandeep
Jain, Meenakshi
Khan, Shabana I.
Jacob, Melissa R.
Tekwani, Babu L.
Singh, Savita
Singh, Prati Pal
Jain, Rahul
Publication Title: 
PloS One

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P.

Author(s): 
Witkowski, Benoit
Lelièvre, Joel
Nicolau-Travers, Marie-Laure
Iriart, Xavier
Njomnang Soh, Patrice
Bousejra-Elgarah, Fatima
Meunier, Bernard
Berry, Antoine
Benoit-Vical, Françoise
Publication Title: 
Malaria Journal

BACKGROUND: Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance.

Author(s): 
Muehlenbachs, Atis
Nabasumba, Carolyn
McGready, Rose
Turyakira, Eleanor
Tumwebaze, Benon
Dhorda, Mehul
Nyehangane, Dan
Nalusaji, Aisha
Nosten, Franois
Guerin, Philippe J.
Piola, Patrice
Publication Title: 
PloS One

Malarial pigment (natural haemozoin, HZ) is a ferriprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism. HZ-fed human monocytes are functionally compromised, releasing increased amounts of pro-inflammatory molecules, including cytokines, chemokines and cytokine-related proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9), whose role in complicated malaria has been recently suggested. In a previous work HZ was shown to induce through TNFalpha production the release of monocytic lysozyme, an enzyme stored in gelatinase granules with MMP-9.

Author(s): 
Polimeni, Manuela
Valente, Elena
Aldieri, Elisabetta
Khadjavi, Amina
Giribaldi, Giuliana
Prato, Mauro
Publication Title: 
PloS One

BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation.

Author(s): 
Thomas, Vincent
Góis, Ana
Ritts, Bruce
Burke, Peter
Hänscheid, Thomas
McDonnell, Gerald

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