RESUMO
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Assuntos
Doença de Chagas/tratamento farmacológico , Kinetoplastida/efeitos dos fármacos , Kinetoplastida/enzimologia , Leishmaniose/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Pirimidinas/farmacologia , Triazóis/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Animais , Doença de Chagas/parasitologia , Quimotripsina/antagonistas & inibidores , Quimotripsina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Concentração Inibidora 50 , Leishmaniose/parasitologia , Camundongos , Estrutura Molecular , Terapia de Alvo Molecular , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/classificação , Pirimidinas/efeitos adversos , Pirimidinas/química , Pirimidinas/uso terapêutico , Especificidade da Espécie , Triazóis/efeitos adversos , Triazóis/química , Triazóis/uso terapêutico , Tripanossomíase Africana/parasitologiaRESUMO
Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.
RESUMO
BACKGROUND: Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.7. METHODS: The effects of SMIP-7.7 at concentrations between 0.90% and 0.09% were compared to the vehicle control or Aldara(®) (3M Health Care Limited, Northridge, CA, USA) as treatment for genital HSV-2 infections. Following intravaginal inoculation of Hartley guinea pigs with 10(6) pfu HSV-2 (MS strain), animals were treated intravaginally beginning at 36 h post-infection. Animals were evaluated for acute disease, acute virus replication, recurrent disease and shedding, as well as infection of the dorsal root ganglia. RESULTS: Treatment with SMIP-7.7 significantly decreased mean total lesion scores during primary infection (all doses, P<0.01 compared with vehicle control, and similar to Aldara(®)). Vaginal virus titres were reduced in treated animals compared with vehicle control (P<0.001 for each treatment versus vehicle control on day 4). Treatment with SMIP-7.7 also significantly decreased the number of recurrent lesion days, the number of days with recurrent virus shedding and the infection of the dorsal root ganglia compared to the vehicle control, and was similar to Aldara(®). As opposed to Aldara(®), SMIP-7.7 did not induce fever or weight loss during treatment. CONCLUSIONS: SMIP-7.7 improves the outcome of primary and recurrent HSV-2 disease comparable to Aldara(®) but without some of the side effects associated with Aldara(®).
Assuntos
Antivirais/farmacologia , Modelos Animais de Doenças , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Receptor 7 Toll-Like/agonistas , Administração Tópica , Animais , Antivirais/administração & dosagem , Cobaias , Herpes Genital/tratamento farmacológico , Herpes Genital/imunologia , Herpes Genital/virologia , Herpesvirus Humano 2/isolamento & purificação , Receptor 7 Toll-Like/imunologiaRESUMO
Model studies for the syntheses of phosphonate analogs of sphingomyelin and ceramide 1-phosphate are described. The pentacovalent oxaphospholene 3b (derived from methyl vinyl ketone and triethyl phosphite) readily condensed with dialkyl azodicarboxylates (R = Et, t-Bu, CH(2)CCl(3)) to form beta-hydrazido gamma-ketophosphonates 5 and 8 in excellent yields. Cleavage of the N-N bond in 5a (R = Et) or 5b (R = t-Bu) via standard methods was unsuccessful. Upon reduction with NaBH(4), 8 produced the oxazolidinone 9 (93%) as a diastereomeric mixture of 3:1. Treatment of 9 with Zn/HOAc/acetone at rt readily cleaved the N-N bond to form 11 (78-83%). Confirmation of stereochemical assignments in 11 (3:1, trans:cis) was accomplished via NOE experiments.