title: A novel carbon monoxide-releasing molecule fully protects mice from severe malaria.
abstract: Severe forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasite Plasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO delivery in vivo without affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection.
authors.affiliation: Unidade de Imunologia Molecular, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Pena
authors.forename: Nuno
authors.initials: N
authors.lastname: Penacho
authors.forename: Liliana
authors.initials: L
authors.lastname: Mancio-Silva
authors.forename: Rita
authors.initials: R
authors.lastname: Neres
authors.forename: João D
authors.initials: JD
authors.lastname: Seixas
authors.forename: Afonso C
authors.initials: AC
authors.lastname: Fernandes
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Romão
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.forename: Ana
authors.initials: A
authors.lastname: Pamplona
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000378:metabolism*; D002263:Carboxyhemoglobin / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D013862:Thiogalactosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C574452:ALF492; D000962:Antimalarials; D009942:Organometallic Compounds; D013862:Thiogalactosides; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D051547:Heme Oxygenase-1