Inhibition of herpes simplex

Inhibition of herpes simplex virus type 1 replication in vitro and in vivo of geldanamycin
Geldanamycin (GA) is an antibiotic, it targets the role of heat shock protein of Hsp90 N-terminal ATP / ADP binding sites. Antibiotic selection in our fight against the virus, it is found that the geldanamycin significant anti-herpes simplex virus type 1 (HSV-1). In vitro in Vero cells within the GA significantly inhibit the replication of HSV-1, the IC50 was 0.05 93μmol / L, GA CC50 toxicity on Vero cells for 35 μmol / L, the therapeutic index of up to 3763. HSV-1 intraperitoneal (ip) infection 1h after intraperitoneal (ip) injection of GA (0 .0 93 0 .37 mg / kg) can be increased to 67% to 100% survival rate, subcutaneous (sc) administration (0 .37 mg / kg), the survival rate was 3.8%, significantly higher than the saline control group (ipP0 .0 0 1 sc P0 .0 5). GA mice with acute L, the D50 is 15 .5 mg / kg (ip). Geldanamycin does not affect virus adsorption and penetration. GA can inhibit the in vitro and in vivo herpes simplex virus type 1, the GA can be a new anti-herpes simplex virus infection drug

 

 

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Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoeliiAnti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii

Abstract (provisional)
 Background
 Geldanamycin (GA), a quinone adriamycin antibiotic shown in vitriol that possess anti-Plasmodium activity. Pharmacological activity of this drug will inhibit its ability to PfHsp90 due. The parasite growth arrest has 

been shown to be due to drug-induced constipation the transition from ring to trophozoite stage. To further evaluate the consequences of this feature have 

pharmacodynamic the antimalarial

 activity of  Geldanamycin-induced analogues with improved properties of a drug in Plasmodium-infected animal models for their ability to release the parasites were evaluated. In this case, the hypothesis was then tested with

 regard to the susceptibility of the cured animals reflects malaria in an attenuated parasite load that can be caused by a protective

 immune response in the host.
 Methods
 Six weeks old Swiss mice were infected with a lethal Plasmodium yoelii (17XL) strain. On the occurrence of clinical symptoms 

of malaria, these animals were treated with two different  Geldanamycin derivatives and the parasite load was monitored 15-16 days. Drug-treated animals were then cured of the parasite with a lethal dose of P. yoelii 17XL called into question. Serum samples from GA

 cured mice with P. yoelii 17XL called into question were examined for the presence of antibodies against the parasite proteins by

 Western blot analysis.
 Results
 The treatment of P. yoelii 17XL infected mice with GA derivatives showed slow recovery from the clinical symptoms of the disease. 

Blood smears from drug-treated mice showed a predominance of parasite-ring when compared to the control group. Although P. yoelii affects preference enormousness (mature erythrocytes) in the 

development of drugs-treated animals showed an increased invasion of reticulocytes. Cured animals demonstrated robust protection against subsequent

 infections and serum samples from these animals showed antibodies against a large majority of parasite proteins.

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Geldanamycin introduction

Hsp90 proteins play an important role in regulating the cell cycle, cell growth, cell survival, apoptosis, angiogenesis, and oncogenesis. Geldanamycin induces the degradation of proteins in tumor cells such as v-Src, Bcr-Abl and p53 are mutated in preference to their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent anti-tumor potential of geldanamycin shows some important drawbacks as active ingredient (ie, hepatotoxicity), which led to the development of geldanamycin analogs, particularly analogs that derivatization at position 17: Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus. Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and inhibits its function. There is a macrocyclic polyketide that is synthesized from a type I polyketide synthase. The genes, Gela, yellow, and GELC for polyketide synthase encoding. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then uses malonyl-CoA, methylmalonyl-CoA and methoxymalonyl CoA to synthesize the precursor Progeldanamycin.  This precursor is subjected to several enzymatic and non-enzymatic adaptation to the active molecule geldanamycin, which catalyze hydroxylation include o-methylation, carbamoylation, and generate oxidation.

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