177,100 research outputs found
Synthesis and anti-HIV activity evaluation of new phenyl ethyl thiourea (PET) derivatives
No full textThis manuscript describes the synthesis of a new series of phenyl ethyl thiourea (PET) derivatives, with the aim to extend the SAR studies of the well known PET molecules endowed with anti-HIV activity. Preliminary results indicated that the synthesized compounds possess low anti-HIV activity
Alarmins and MicroRNAs, a New Axis in the Genesis of Respiratory Diseases: Possible Therapeutic Implications
No full textIt is well ascertained that airway inflammation has a key role in the genesis of numerous respiratory pathologies, including asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Pulmonary tissue inflammation and anti-inflammatory responses implicate an intricate relationship between local and infiltrating immune cells and structural pulmonary cells. Alarmins are endogenic proteins discharged after cell injury in the extracellular microenvironment. The purpose of our review is to highlight the alterations in respiratory diseases involving some alarmins, such as high mobility group box 1 (HMGB1) and interleukin (IL)-33, and their inter-relationships and relationships with genetic non-coding material, such as microRNAs. The role played by these alarmins in some pathophysiological processes confirms the existence of an axis composed of HMGB1 and IL-33. These alarmins have been implicated in ferroptosis, the onset of type 2 inflammation and airway alterations. Moreover, both factors can act on non-coding genetic material capable of modifying respiratory function. Finally, we present an outline of alarmins and RNA-based therapeutics that have been proposed to treat respiratory pathologies
Mechanism of falcipain-2 inhibition by α,β-unsaturated benzo[1,4]diazepin-2-one methyl ester
No full textFalcipain-2 (FP-2) is a papain-family cysteine protease of Plasmodium falciparum whose primary function is to degrade the host red cell hemoglobin, within the food vacuole, in order to provide free amino acids for parasite protein synthesis. Additionally it promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane. Therefore, the inhibition of FP-2 represents a promising target in the search of novel anti-malarial drugs. A potent FP-2 inhibitor, characterized by the presence in its structure of the 1,4-benzodiazepine scaffold and an a,b-unsaturated methyl ester moiety capable to react with the Cys42 thiol group located in the active site of FP-2, has been recently reported in literature. In order to study in depth the inhibition mechanism triggered by this interesting compound, we carried out, through ONIOM hybrid calculations, a computational investigation of the processes occurring when the inhibitor targets the enzyme and eventually leads to an irreversible covalent Michael adduct. Each step of the reaction mechanism has been accurately characterized and a detailed description of each possible intermediate and transition state along the pathway has been reported
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Inhibition of Rhodesain as a Novel Therapeutic Modality for Human African Trypanosomiasis
No full textRhodesain, a cathepsin L-like cysteine protease of T. brucei rhodesiense, is considered a potential target for the treatment of human African trypanosomiasis. Recent findings have confirmed that rhodesain, a lysosomal protease, is essential for parasite survival. Rhodesain is required by T. brucei to cross the blood-brain barrier, degrade host immunoglobulins, and turn over variant surface coat glycoproteins of T. brucei, which impair effective host immune responses. In this Perspective, we discuss the main classes of rhodesain inhibitors, including peptidic, peptidomimetic, and nonpeptidic structures, emphasizing those that have exhibited an optimal match between enzymatic affinity and trypanocidal profile and those for which preclinical investigations are currently in progress
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The inhibition of cysteine proteases rhodesain and TbCatB : A valuable approach to treat human african trypanosomiasis
No full textHuman African Trypanosomiasis (HAT) is an endemic parasitic disease of sub-Saharan Africa, caused by two subspecies of protozoa belonging to Trypanosoma genus: T. brucei gambiense and T. brucei rhodesiense. In this context the inhibition of the papain-family cysteine proteases rhodesain and TbCatB has to be considered a promising strategy for HAT treatment. Rhodesain, the major cathepsin L-like cysteine protease of T. brucei rhodesiense, is a lysosomal protease essential for parasite survival. It is involved in parasite invasivity, allowing it to cross the blood-brain barrier (BBB) of the human host, causing the second lethal stage of the disease. Moreover, it plays an important role in immunoevasion, being involved in the turnover of variant surface glycoproteins of the T. brucei coat and in the degradation of immunoglobulins, avoiding a specific immune response by the host cells. On the other hand TbCatB, a cathepsin B-like cysteine protease, present in minor abundance in T. brucei, showed a key role in the degradation of host transferrin, which is necessary for iron acquisition by the parasite. In this review article we now discuss the most active peptide, peptidomimetic and non-peptide rhodesain and TbCatB inhibitors as valuable strategy to treat HAT, due also to the complementary role of the two T. brucei proteases
Synthesis and biological evaluation of new 2-amino-6-(trifluoromethoxy)benzoxazole derivatives, analogues of riluzole
No full textThis manuscript describes the synthesis of a new series of 2-amino-6-(trifluoromethoxy)benzoxazole derivatives (1–5) and a benzothiazine derivative (6) structurally related to riluzole, the only neuroprotective drug currently approved for the treatment of the amyotrophic lateral sclerosis. Preliminary results indicate that the synthesized compounds, in particular benzamide derivatives 3 and 4, are able to antagonize voltage-dependent Na+ channel currents, and therefore they could be exploited as new inhibitors of these channels. Moreover, all compounds possess low binding affinity for GABA and NMDA receptors
DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF PEPTIDOMIMETIC FALCIPAIN-2 INHIBITORS AS ANTIMALARIAL AGENTS
No full textMalaria is currently endemic in 106 countries, with an estimated 216 million clinical
cases and nearly 655000 deaths in 2010 [1]. Five species of a parasite of Plasmodium
genus are infective for humans, with the most severe form of malaria caused by P.
falciparum species.The increasing resistance of malaria parasites to antimalarial drugs,
the lack of widely available vaccines that provide a high level of protection for a
sustained period, and the inadequate control of mosquito vectors demand new
approaches to drug development. One promising strategy to develop new drugs has
been to target proteases of malaria parasites which play pivotal roles in the processes
of host erythrocyte rupture, erythrocyte invasion, and hemoglobin degradation.
Falcipain-2 (FP-2) of P. falciparum is a papain-family (clan CA, family C1) cysteine
protease and is likely the major hemoglobinase in the food vacuole of erythrocytic
parasites. FP-2 is also able to promote host cell rupture cleaving erythrocyte
membrane skeletal proteins. Therefore, the inhibition of FP-2 represents a promising
strategy for discovery of novel anti-malarial drugs.
Our research group has actively been involved on the synthesis of novel
peptidomimetic FP-2 inhibitors containing a 1,4-benzodiazepine scaffold [2-6],
introduced internally to a peptide sequence which mimics the dipeptide D-Ser-Gly, and
different electrophilic warheads able to interact with the thiol group of the cysteine
active site by forming a reversible or irreversible covalent bond.
Several of the newly synthesized peptidomimetics turned out to be potent and selective
FP-2 inhibitors and showed a good selectivity towards human cathepsin B and L. The
obtained results have been rationalized on the basis of docking experiments. These
studies helped us to identify the structural requirements that are essential for the
interaction with the target and in determining the binding mode of these type of
inhibitors
- …
