6 research outputs found
Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes?
The genome of human immunodeficiency virus type 1 (HIV-1) encodes 15 distinct proteins, three of which provide essential enzymatic functions: a reverse transcriptase (RT), an integrase (IN), and a protease (PR). Since these enzymes are all homodimers, pseudohomodimers or multimers, disruption of protein-protein interactions in these retroviral enzymes may constitute an alternative way to achieve HIV-1 inhibition. A growing number. of dimerization inhibitors for these enzymes is being reported. This mini review summarizes some approaches that have been followed for the development of compounds that inhibit those three enzymes by interfering with the dimerization interfaces between the enzyme subunits. (c) 2006 Elsevier B.V. All rights reserved
TSAO compounds: The comprehensive story of a unique family of HIV-1 specific inhibitors of reverse transcriptase
Emergence of drug-resistant viral strains is one of the major milestones and the main cause for the failure of antiretroviral therapy. Combination of different anti-HIV agents has E become the standard clinical practice to keep the viral load at low or even undetectable levels and to prevent emergence of virus-drug resistance. Among the human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors, the so called nonnucleoside RT inhibitors (NNRTIs) have gained a definitive place in the treatment of HIV infections in combination with nucleoside analogue RT inhibitors (NRTIs) and HIV protease inhibitors (PIs). The virus can be markedly suppressed for a relatively long period of time when exposed to multiple drug combination therapy (highly active antiretroviral therapy, HAART). TSAO derivatives are a peculiar group of highly functionalized nucleosides that belong to the so-called nonnucleoside RT inhibitors (NNRTIs). They exert their unique selectivity for HIV-1 through a specific interaction with the p51 subunit of HIV-1 RT. They are the first small molecules that seem to interfere with the dimerization process of the enzyme. This review covers the work carried out with this unique class of specific inhibitors of HIV-1 reverse transcriptase, including structure activity relationship studies (SAR), its mechanism of action, resistance studies, model of interaction with the enzyme, etc
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091
We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor
and anti-metastatic activities of a new series of chalcones, whose prototype compound
is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-
2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these
chalcones bind to the colchicine site of tubulin and therefore prevent the curved-tostraight
structural transition of tubulin, which is required for microtubule formation.
Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M
phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular
disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay
at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091
(i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer
xenograft models by causing rapid intratumoral vascular shutdown and massive
tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of
combretastatin A4-phosphate. Our data indicate that this novel class of chalcones
represents interesting lead molecules for the design of vascular disrupting agents
(VDAs). Moreover, we provide evidence that our prodrug approach may be valuable
for the development of anti-cancer drugs.M-DC thanks the Fondo Social Europeo (FSE) and
the JAE Predoc Programme for a predoctoral fellowship.
This work has received the Ramón Madroñero award for
young researchers (to M-DC and OB) in the XVII call
www.impactjournals.com/oncotarget 17 Oncotarget
sponsored by the Spanish Society of Medicinal Chemistry
(SEQT). This project has been supported by the Spanish
Ministerio de Economia y Competitividad (SAF2012-
39760-C02-01 to M-JC, M-JP-P, SV and E-MP; and
BIO2013-42984-R to JFD), Comunidad de Madrid
(BIPEDD2; ref. P2010/BMD-2457 to M-JC and J-FD),
the Swiss National Science Foundation (310030B_138659
and 31003A_166608; to MOS). The authors acknowledge
networking contribution by the COST Action CM1407
“Challenging organic syntheses inspired by nature - from
natural products chemistry to drug discovery” and COST
action CM1470.Peer reviewe
Diseño y desarrollo de una novedosa estrategia profármaco basada en la enzima DPPIV/CD26
In the present paper a novel prodrug approach is described. The approach consists on the development of peptide-drug conjugates
of compounds bearing amine groups of different nature or hydroxy-groups, also of different nature, which are specifically cleaved by DPPIV/
CD26. This prodrug approach is viable, versatile an useful not only to ameliorate the water solubility of lipophilic or polar molecules, but also
to highly increase the in vivo oral bioavailability of therapeutic agents.En el presente artĂculo se describe una novedosa aproximaciĂłn profármaco, consistente en el desarrollo de conjugados pĂ©ptidofármaco,
de compuestos portadores de grupos amino de distinta naturaleza o de grupos hidroxilo tambiĂ©n de distinta naturaleza que son especĂficamente
hidrolizados por la enzima endógena DPPIV/CD26. La aproximación es viable, versátil y útil no sólo para mejorar la solubilidad
en agua tanto de moléculas lipófilas, como polares, sino también para producir aumentos muy notables de la biodisponibilidad oral in vivo
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091
We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.status: publishe
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091
We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3''-amino-4''-methoxyphenyl)-1-(5'-methoxy-3',4'-methylendioxyphenyl)- 2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-tostraight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs