Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/ CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV- 1 vaccine.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

HIV - recentes avanços na pesquisa de fármacos

The development of new antiretroviral drugs is a dynamic process that is continuously fueled by identification of new molecular targets and new compounds for know targets. The current available drugs can be classified into five categories: nucleoside analogues reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and entry inhibitors (fusion inhibitors and CCR5 antagonist). In addition, the maturation inhibitors may be considered as potential target for chemotherapeutic intervention. This review presents some anti-HIV agents that have already gone through the advance development process for final approval for the treatment of AIDS.

Steroidal and phenolic compounds from Sidastrum paniculatum (L.) Fryxell and evaluation of cytotoxic and anti-inflammatory activities

Sidastrum paniculatum (L.) Fryxell belongs to the family Malvaceae and is popularly known as "malva roxa" or "malvavisco". The phytochemical study of the hexane, CHCl3 and EtOAc phases from the crude ethanol extract of S. paniculatum led to the isolation of six compounds: a mixture of β-sitosterol and stigmasterol, 4-methoxy-3-hydroxybenzoic acid, 4-methoxy-3-hydroxybenzaldehyde, N-trans-feruloyltyramine and kaempferol-3-O-β-D-(6''-E-p -coumaroyl) glucoside. The structural identification of the compounds was made on the basis of spectroscopic methods such as IR, ¹H and 13C NMR with the aid of including two-dimensional techniques, besides comparison with literature data. The β-sitosterol and stigmasterol mixture showed a significant anti-inflammatory activity.

Synthesis and biological activity of n-{5-(4-methylphenyl) diazenyl-4-phenyl-1, 3-thiazol-2-yl}benzamide derivatives

In the present study, various amides of 2-amino-5-(4-methylphenyl)-diazenyl-4-phenyl-1, 3-thiazole was synthesized and their biological activities were evaluated. All the synthesized compounds were characterized by the combination of elemental analysis and standard spectroscopic methods. They are screened for anti-bacterial activity against Escherichia coli and Staphylococcus aureus as well as screened for antifungal activity against Aspergillus niger and Apergillus oryzae by cup plate method at 1 µg/ mL concentration in DMF.

Constituintes químicos das folhas e avaliação da atividade anti-inflamatória de extratos das raízes e folhas de Guettarda pohliana Müll. Arg. (Rubiaceae)

This phytochemical investigation of Guettarda pohliana leaves led to the isolation of the triterpenes pomolic acid, rotundic acid, 3β,6α,19α,23-tetrahydroxyurs-12-en-28-oic acid, clethric acid, ursolic acid and oleanolic acid, the monoterpenoids loliolide and secoxyloganin, besides daucosterol and steroids. The structures of the isolated compounds were assigned on the basis of NMR data, including two-dimensional NMR methods. The anti-inflammatory activity of the crude methanolic extracts from leaves and roots, as well as of their fractions, was evaluated.

Estudo fitoquímico e avaliação da atividade anti-inflamatória de Aeschynomene fluminensis vell. (Fabaceae)

Phytochemical investigation of Aeschynomene fluminensis leaves and branches led to isolation of the flavonoid glycosides kaempferol 3,7-di-O-α-L-rhamnopyranoside, kaempferol 7-O-α-L-rhamnopyranoside, kaempferol 3-O-apiofuranosil-7-O- rhamnopyranoside, quercitin 3-O-α-L-rhamnopyranoside, quercitin 3-O-arabinofuranoside, 8-β-D-glucopyranosyl 4',5,7-trihydroxyflavanone, the isoflavonoid 4',7-di-hydroxy-isoflavone, the dimer epicatechin-(2β→7, 4β→8)- epicatechin, the polyol 3-O-methyl-chiro-inositol and two steroids in sitosterol and stigmasterol mixture. These compounds were identified by NMR ¹H and 13C and compared with literature data. Anti-inflammatory activity of the crude methanolic extract and its fractions was evaluated.

Constituintes químicos e avaliação das atividades antioxidante e anti-inflamatória das raízes de Sabicea brasiliensis wernh (Rubiaceae)

The phytochemical investigation of Sabicea brasiliensis roots led to the isolation of 5-O-caffeoylquinic acid, 3,5- and 4,5-O-dicaffeoylquinics acids, scopoletin, ursolic acid, a mixture of β-sitosterol, stigmasterol and campesterol, daucosterol and saccharose. The structures of the isolated compounds were assigned on the basis of one- and two-dimensional NMR spectroscopic methods and by comparison with literature data. The anti-inflammatory and antioxidant activities of the crude methanolic extract and its fractions were analyzed.

CHEMICAL CONSTITUENTS, ANTI-INFLAMMATORY, AND FREE-RADICAL SCAVENGING ACTIVITIES OF Guettarda viburnoides CHAM. & SCHLTDL. (RUBIACEAE)

Chemical investigation of Guettarda viburnoides (leaves) led to the isolation of ursolic acid, uncaric acid, secoxyloganin, and grandifloroside, along with a mixture of quercetin-3-O-β-D-galactopyranoside and quercetin-3-O-β-D-glucopyranoside, and of β-sitosterol and stigmasterol. The structures of the isolated compounds were elucidated on the basis of their NMR data. The crude extract, ethyl acetate fraction, aqueous-methanol fraction, and grandifloroside showed significant DPPH free-radical scavenging activities with IC50 ranging from 18.92 to 26.47 µg mL-1. The topical administration of the crude extract and fractions markedly reduced the croton oil-induced mice ear edema in 67.0%-99.0%. Inhibition of tissue MPO activity was also observed, which demonstrated an anti-inflammatory effect of the G. viburnoides species.

Anti-inflammatory and antinociceptive activities of an acid fraction of the seeds of Carpotroche brasiliensis (Raddi) (Flacourtiaceae)

Carpotroche brasiliensis is a native Brazilian tree belonging to the Oncobeae tribe of Flacourtiaceae. The oil extracted from its seeds contains as major constituents the same cyclopentenyl fatty acids hydnocarpic (40.5%), chaulmoogric (14.0%) and gorlic (16.1%) acids found in the better known chaulmoogra oil prepared from the seeds of various species of Hydnocarpus (Flacourtiaceae). These acids are known to be related to the pharmacological activities of these plants and to their use as anti-leprotic agents. Although C. brasiliensis oil has been used in the treatment of leprosy, a disease that elicits inflammatory responses, the anti-inflammatory and analgesic activities of the oil and its constituents have never been characterized. We describe the anti-inflammatory and antinociceptive activities of C. brasiliensis seed oil in acute and chronic models of inflammation and in peripheral and central nociception. The mixture of acids from C. brasiliensis administered orally by gavage showed dose-dependent (10-500 mg/kg) anti-inflammatory activity in carrageenan-induced rat paw edema, inhibiting both the edema by 30-40% and the associated hyperalgesia. The acid fraction (200 mg/kg) also showed significant antinociceptive activity in acetic acid-induced constrictions (57% inhibition) and formalin-induced pain (55% inhibition of the second phase) in Swiss mice. No effects were observed in the hot-plate (100 mg/kg; N = 10), rota-road (200 mg/kg; N = 9) or adjuvant-induced arthritis (50 mg/kg daily for 7 days; N = 5) tests, the latter a chronic model of inflammation. The acid fraction of the seeds of C. brasiliensis which contains cyclopentenyl fatty acids is now shown to have significant oral anti-inflammatory and peripheral antinociceptive effects.