New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant

Targeting the disordered N-terminal domain of androgen receptor. Novel inhibitors tackling biomolecular condensation to treat late stage prostate cancer

[eng] Drug discovery is the process by which new drugs are found and developed into the market. Given the scope of this thesis, the term “drug” will refer to small molecules and the term “target” to proteins, otherwise noted. Currently, most drug discovery strategies rely on the resolved three-dimensional structure of the target. Structure-based drug discovery (SBDD) is advantageous as it accelerates and lowers the cost of the drug discovery process. However, the essential requisite for SBDD, the prior knowledge of the target protein structure, has narrowed the types of proteins in drug discovery programs to globular proteins. It is estimated that 33-50% of our proteome is intrinsically disordered. Intrinsically disordered proteins (IDPs) and protein regions (IDRs) do not spontaneously fold into a stable secondary and tertiary structure in their native state yet are functionally active. IDPs have long been considered undruggable as their lack of a stable tertiary structure impedes the application of SBDD. Nevertheless, IDPs participate in many physiological processes, as well as in diseases. Hence finding new approaches to target IDPs is crucial to expand the druggable proteome and fill unmet needs across diseases in which disorder plays a role

Targeting the disordered N-terminal domain of androgen receptor. Novel inhibitors tackling biomolecular condensation to treat late stage prostate cancer

Programa de Doctorat en Química Orgànica / Tesi realitzada a l'Institut de Recerca Biomèdica de Barcelona (IRBB)[eng] Drug discovery is the process by which new drugs are found and developed into the market. Given the scope of this thesis, the term “drug” will refer to small molecules and the term “target” to proteins, otherwise noted. Currently, most drug discovery strategies rely on the resolved three-dimensional structure of the target. Structure-based drug discovery (SBDD) is advantageous as it accelerates and lowers the cost of the drug discovery process. However, the essential requisite for SBDD, the prior knowledge of the target protein structure, has narrowed the types of proteins in drug discovery programs to globular proteins. It is estimated that 33-50% of our proteome is intrinsically disordered. Intrinsically disordered proteins (IDPs) and protein regions (IDRs) do not spontaneously fold into a stable secondary and tertiary structure in their native state yet are functionally active. IDPs have long been considered undruggable as their lack of a stable tertiary structure impedes the application of SBDD. Nevertheless, IDPs participate in many physiological processes, as well as in diseases. Hence finding new approaches to target IDPs is crucial to expand the druggable proteome and fill unmet needs across diseases in which disorder plays a role

Intrinsically disordered proteins and biomolecular condensates as drug targets

Intrinsically disordered domains represent attractive therapeutic targets because they play key roles in cancer, as well as in neurodegenerative and infectious diseases. They are, however, considered undruggable because they do not form stable binding pockets for small molecules and, therefore, have not been prioritized in drug discovery. Under physiological solution conditions many biomedically relevant intrinsically disordered proteins undergo phase separation processes leading to the formation of mesoscopic highly dynamic assemblies, generally known as biomolecular condensates that define environments that can be quite different from the solutions surrounding them. In what follows, we review key recent findings in this area and show how biomolecular condensation can offer opportunities for modulating the activities of intrinsically disordered targets.Copyright © 2021 Elsevier Ltd. All rights reserved

Azapropellanes with anti-influenza a virus activity

The synthesis of several [4,4,3], [4,3,3], and [3,3,3]azapropellanes is reported. Several of the novel amines displayed low-micromolar activities against an amantadine-resistant H1N1 strain, but they did not show activity against an amantadine-sensitive H3N2 strain. None of the tested compounds inhibit the influenza A/M2 proton channel function. Most of the compounds did not show cytotoxicity for MDCK cells.status: publishe

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.publisher: Elsevier articletitle: New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2015.04.030 content_type: article copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.status: publishe

Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel

Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.status: publishe

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant

Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.This work was supported by IRB, ICREA (X.S.), Obra Social “la Caixa” (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marató de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain)