Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Chakrabarty, Subhra Prakash; Ramesh, Ramapanicker; Mishra, Roli; Chandrasekaran, Srinivasan; Balaram, Hemalatha

doi:10.1016/j.bmc.2009.10.003

Cited by 33 publications

(34 citation statements)

References 43 publications

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“…Here, the peptides contained a lysine residue functionalized at the ε-amino group as a propargyloxycarbonyl (alkyne) derivatives. These were selectively conjugated with azide derivatives of carbohydrates or thymidine, using Cu(I) catalyzed click reactions [62]. Such compounds function as potent inhibitor of sir2, NAD + dependent deacetylases of the malaria parasite.…”

Section: Bioconjugation To Combine Units With Different Functionsmentioning

confidence: 99%

Click Chemistry in Peptide-Based Drug Design

2013

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Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.

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Section: Bioconjugation To Combine Units With Different Functionsmentioning

confidence: 99%

Click Chemistry in Peptide-Based Drug Design

2013

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“…For example, surfactin and nicotinamide have similar activity against PfSir2A (IC 50 35 and 51 μ m , respectively); however splitomycin and sirtinol are less active (IC 50 >400 and >50 μ m , respectively) 17 , 19 . In a recent study, lysine‐based tripeptide analogues were synthesized to try to target PfSir2 through competition with the peptide binding pocket 69 . Three of four analogues examined had similar or better activity (IC 50 23–34 μ m ) against PfSir2A compared with surfactin and nicotinamide 69 .…”

Section: Anti‐parasitic Activity Of Hdac Inhibitorsmentioning

confidence: 99%

HDAC inhibitors in parasitic diseases

2011

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Parasitic diseases cause significant global morbidity and mortality, particularly in underdeveloped regions of the world. Malaria alone causes B800 000 deaths each year, with children and pregnant women being at highest risk. There is no licensed vaccine available for any human parasitic disease and drug resistance is compromising the efficacy of many available anti-parasitic drugs. This is driving drug discovery research on new agents with novel modes of action. Histone deacetylase (HDAC) inhibitors are being investigated as drugs for a range of diseases, including cancers and infectious diseases such as HIV/AIDS, and several parasitic diseases. This review focuses on the current state of knowledge of HDAC inhibitors targeted to the major human parasitic diseases malaria, schistosomiasis, trypanosomiasis, toxoplasmosis and leishmaniasis. Insights are provided into the unique challenges that will need to be considered if HDAC inhibitors are to be progressed towards clinical development as potential new anti-parasitic drugs.

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“…However, recent studies [65,66] have shown that both nicotinamide and the synthetic inhibitor surfactin inhibit PfSir2 activity and are potent inhibitors of intra-erythrocytic growth of the parasite. Chakrabarty et al [67] have also developed lysine-based tripeptide analogues as PfSir2 inhibitors, one of which also markedly inhibited parasite intra-erythrocytic growth. Moreover, sirtinol was found to inhibit the in vitro growth of Leishmania infantum via the induction of apoptosis [68].…”

Section: -Sirtuin Inhibitorsmentioning

confidence: 98%

Targeting Schistosome Histone Modifying Enzymes for Drug Development

Pierce

Dubois-Abdesselem²,

Lancelot³

et al. 2012

cpd

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The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets. SCHISTOSOMIASIS: IMPACT OF THE DISEASE AND THE NEED FOR NEW DRUGSThe impact of schistosomiasis on communities in endemic areas extends well beyond the classical signs of morbidity: Symmer's fibrosis leading to hepato-splenomegaly, ascites, oesophageal varices, and culminating in death. These overt and catastrophic symptoms affect only a relatively small percentage of infected individuals, even if absolute numbers of annual deaths (about 280 000) are high. However, more cryptic effects such as anaemia, undernutrition, diarrhoea and chronic pelvic or abdominal pain were consistently underevaluated until a meta-analysis of a large number of previous schistosomiasis morbidity studies by King et al.[1] allowed an objective assessment. This showed that the WHO's previously estimated disability weight for schistosomiasis of 0.5%, based essentially on mortality, should be markedly revised upwards to between 2 and 15% and that the years of life lost to schistosomiasis represented a relatively small proportion of the total of years lost to disability. This reassessment of the true disease burden represented by schistosomiasis has led to the realization of the importance of reinforcing control measures.In the continuing absence of an effective infection-preventing vaccine, the only viable strategy is the mass-treatment of populations in endemic areas using the currently available drug, praziquantel. Thus the Schistosomiasis Control Initiative in Africa [2] had dispensed more than 40 million praziquantel treatments in eight sub-Saharan countries by 2008. This ongoing programme will undoubtedly have a major impact, both on...

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Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Cited by 33 publications

References 43 publications

Click Chemistry in Peptide-Based Drug Design

Click Chemistry in Peptide-Based Drug Design

HDAC inhibitors in parasitic diseases

Targeting Schistosome Histone Modifying Enzymes for Drug Development

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