Current Enzyme Inhibition (v.6, #4)
Editorial [Hot Topic: Enzyme Inhibitors as New Drugs for Microbial Diseases Control: Part I (Guest Editor: Alane Beatriz Vermelho)] by Alane Beatriz Vermelho (170-170).
Enzymes from a variety of microorganisms have been characterized and explored as novel chemotherapeutic targets. In this context enzyme inhibitors have become a hot research area due to their immense potential for microbial disease control. This special issue of Current Enzyme Inhibition entitled and#x201C;Enzyme inhibitors as new drugs for microbial disease control (Part I)and#x201D;, brings together three reviews that focus on several important aspects of enzyme inhibition in Chagas disease and leishmaniasis, human immunodeficiency virus, type 1 (HIV-1) and pathogenic bacteria. The first review by Maia and Fraga describe the use of the molecular hybridization approach as a powerful medicinal chemistry tool for designing ligands and prototypes able to act on at least two different molecular targets. Drug resistance is an increasing problem affecting the treatment of microorganisms of medical importance such as viruses, bacteria and other parasites. Consequently, the development of new chemotherapeutic agents that are more potent and less prone to resistance than the current drugs is an important matter. The review describes the use of a hybrid therapy strategy where a single chemical entity could modulate two or more biological targets to control the disease. An example of the hybrid approach is the Anti-HIV Prototype which involves the dual inhibition of HIV-1 through reverse transcriptase (RT) and integrase (IN). In the second review Rodrigues et al. made a comprehensive description of the Cysteine peptidases inhibitors studied as a possible chemotherapeutic agents to control Chagas disease. Also other peptidase inhibitors against metallo-, aspartic and threonine (proteasome) peptidases that currently are in progress and could be promising targets in the future were described. In the last review, Merlino et al. discusses the validity of several enzymes and pathways as chemotherapy targets against Chagas disease. Prenyl converting and transferring enzymes, cAMP- specific phosphodiesterases, polyamine and trypanothione synthetic pathways, triosephosphate isomerase, and#945;-hydroxy acid dehydrogenases and trans-sialidase were evaluated in this review. As the Guest Editor, I invited researchers from different universities that were working with inhibitors of microbial enzymes to describe the recent advances in their specific areas of this field. I am very grateful to all of these authors for providing their reviews that combined have provided such an excellent perspective of this important field. We would also like to thank the referees who have critically evaluated the papers.
Discovery of Dual Chemotherapy Drug Candidates Designed by Molecular Hybridization by Rodolfo do Couto Maia, Carlos Alberto Manssour Fraga (171-182).
Molecular hybridization approach is a powerful medicinal chemistry tool for designing ligands and prototypes able to act in at least two different molecular targets, promoting a beneficial effect to the treatment of multifactorial diseases. In this context, this review describes some examples where the use of this molecular modification approach lead to the design of novel chemotherapy prototypes able to act simultaneously in more than one target enzyme useful to control diseases promoted by bacterial, viral, protozal or fungal pathogens.
Peptidase Inhibitors as a Possible Therapeutic Strategy for Chagas Disease by Giseli Capaci Rodrigues, Alcino Palermo Aguiar, Joao Lidio da Silva Goncalves Vianez, Andrew Macrae, Ana Cristina Nogueira de Melo, Alane Beatriz Vermelho (183-194).
Chagas disease, caused by Trypanosoma cruzi, is one of the neglected parasitic tropical diseases affecting thirteen million people annually. At present, there are only two compounds used in the clinical treatment to this disease and they were introduced in the 1960s and 1970s. Nifurtimox and Benznidazole have limited effectiveness and serious side effects. New strategies and targets for an effective chemotherapy for American trypanosomiasis need to be developed. Within this framework, the peptidases have aroused great interest as a chemotherapeutic target against Chagas disease. This is because some T. cruzi peptidases have been implicated, among other processes, in host-parasite interactions and parasitic survival in their hosts like cruzipain (cysteine peptidase) and prolyl oligopeptidase (serine peptidase). Besides, some of these peptidases are expressed in all life cycle stages of the parasite and it is essential for replication of the intracellular forms. The inhibition of these enzymes has shown high anti-T. cruzi activity in vitro and in vivo. In this review, we describe some peptidase inhibitors that have potential in the fight against T. cruzi. Emphasis is given to cruzipain inhibitors and the inhibition mechanism proposed for some them. Among these inhibitors are peptidyl irreversible (halomethyl ketone, diazomethane ketones and vinyl sulfones derivatives) and reversible (aryl ureas and oxadiazoles derivatives) inhibitors, besides non-peptidyl inhibitors (thiosemicarbazones, triazole, triazine nitriles and vinyl sulfones derivatives). Some serine peptidase inhibitors are also described (tic-based peptides, prolylprolylisoxazoles and prolylprolylisoxazolines). Other peptidases, including the metallo-, aspartic and threonine (proteosome) peptidases are discussed and along with blocking cruzipain are targets for future therapeutic strategies.
Targets for Anti-T. cruzi Drugs in the Post-Genomic Era by Alicia Merlino, Mercedes Gonzalez, Hugo Cerecetto (195-210).
The information of the complete genome sequences of Trypanosoma cruzi revealed that its genome contains nearly to 10,000 protein-coding genes. This vast amount of new information allows the identification of therapeutic targets in an accurate and undoubtedly forms. The current post-genomic period is a special moment in the anti-T. cruzi drug discovery and development ushering this moment as the anti-Chagas drug discovery era. In this review we describe, from a medicinal chemistry point of view, several identified potential biological targets for drugs development. We discuss the validity and druggability as anti-Chagas objectives of prenyl converting and transferring enzymes, cAMP-specific phosphodiesterases, polyamine and trypanothione synthetic pathways, triosephosphate isomerase, and#945;-hydroxyacid dehydrogenases and trans-sialidase.
Matrix Metalloproteinases and their Tissue Inhibitors in Diabetes, Atherosclerosis and Prediction of the Cardiovascular Risk by Viola Vargova, Marek Pytliak, Viola Mechirova (211-224).
The interaction between cells and extracellular matrix plays a key role in normal development and differentiation of the organism. Changes in extracellular matrix are regulated by the system of proteolytic enzymes that are responsible for proteolysis of many components of extracellular matrix. By regulating the composition and integrity of the extracellular matrix, this group of enzymes is essential for inducing processes of cell proliferation, differentiation and apoptosis. Matrix metalloproteinases (MMPs) represent the main group of regulatory proteases in ECM. Their activity is regulated at multiple levels, including regulation of transcription, secretion, activation and inhibition. In particular, inhibition of MMP is carried out with the tissue inhibitors of metalloproteinase family - TIMPs. However, there is only a little knowledge about the prognostic impact of the TIMPs/matrix metalloproteinase complex in patients with future cardiovascular events or cardiovascular death. Atherosclerotic plaque formation occurs as a result of cellular migration and proliferation accompanied by an accumulation of ECM. MMP-2-dependent vascular degradation of extracellular matrix promotes smooth muscle cells migration and early plaque development. Immunocytochemistry, zymography and in situ hybridization studies have demonstrated an increased expression of different MMPs in human atherosclerotic plaques. Recent works have shown an increase of MMP-9 in unstable carotid plaques. Furthermore, a significant increase in circulating MMP-9 levels was observed in patients after myocardial infarction, patients undergoing carotid endarterectomy with evidence of ongoing spontaneous embolization and other cardiovascular events. MMP-8 has been implicated in atherosclerotic plaque destabilization through its capacity to thin the protecting fibrous cap, thus rendering it more vulnerable to rupture. Increased plaque MMP-8 activity has been observed in asymptomatic patients with plaque progression. Also, plaques prone to rupture express more immunoreactive MMP-8 compared with lesions with more stable morphology. On the other hand, TIMP-1 appears to play an important role in regulation of left ventricle structure and systolic function. Plasma TIMP-1 concentration is also increased in acute coronary syndrome and serum TIMP-1 is associated with the presence of carotid lesions as well. In the Framingham heart study, total TIMP-1 was related to major cardiovascular risk factors, in particular hypertension which may influence vascular and cardiac remodelling via extracellular matrix degradation. In the present article the authors offer an overview of possible mechanisms of action of MMPs and TIMPs and their predictive value in estimating the cardiovascular risk.