7 research outputs found
High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction
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A comparative effectiveness trial of two faecal immunochemical tests for haemoglobin (FIT). Assessment of test performance and adherence in a single round of a population-based screening programme for colorectal cancer
Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid.
Several strategies aimed to “freeze” natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson’s and Alzheimer’s and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3–C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction
Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally "frozen" analogues of L-glutamic acid
Abstract Several strategies aimed to "freeze" natural amino acids into more constrained analogues have been developed with the aim of enhancing in vitro potency/selectivity and, more in general, drugability properties. The case of L-glutamic acid (L-Glu, 1) is of particular importance since it is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a critical role in a wide range of disorders like schizophrenia, depression, neurodegenerative diseases such as Parkinson's and Alzheimer's and in the identification of new potent and selective ligands of ionotropic and metabotropic glutamate receptors (GluRs). To this aim, bicycle compound Ib was designed and synthesised from D-serine as novel [2.3]-spiro analogue of L-Glu. This frozen amino acid derivative was designed to further limit the rotation around the C3-C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction
ボルツマンマシン ノ サイテキカ モンダイ エノ オウヨウ サイテキカ ノ スウリ ト ソノ オウヨウ
Influenza
is an infectious disease that represents an important
public health burden, with high impact on the global morbidity, mortality,
and economy. The poor protection and the need of annual updating of
the anti-influenza vaccine, added to the rapid emergence of viral
strains resistant to current therapy make the need for antiviral drugs
with novel mechanisms of action compelling. In this regard, the viral
RNA polymerase is an attractive target that allows the design of selective
compounds with reduced risk of resistance. In previous studies we
showed that the inhibition of the polymerase acidic protein-basic
protein 1 (PA–PB1) interaction is a promising strategy for
the development of anti-influenza agents. Starting from the previously
identified 3-cyano-4,6-diphenyl-pyridines, we chemically modified
this scaffold and explored its structure–activity relationships.
Noncytotoxic compounds with both the ability of disrupting the PA–PB1
interaction and antiviral activity were identified, and their mechanism
of target binding was clarified with molecular modeling simulations
High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA–PB1 protein–protein interaction
Optimization of Small-Molecule Inhibitors of Influenza Virus Polymerase: From Thiophene-3-Carboxamide to Polyamido Scaffolds
Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein–protein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad-spectrum activity. Here, we report a further dissection of the thiophene-3-carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed