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1.
Antiviral Res ; 86(2): 212-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20219553

RESUMO

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of current combination therapies for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance and serious side effects can compromise the benefits of the first generation compounds in this class (efavirenz and nevirapine). To study potential pathways leading to resistance against the novel diphenylether NNRTI, RO-0335, sequential passage experiments at low multiplicity of infection (MOI) were performed to solicit a stepwise selection of resistance mutations. Two pathways to loss of susceptibility to RO-0335 were observed, containing patterns of amino acid changes at either V106I/A plus F227C (with additional contributions from A98G, V108I, E138K, M230L and P236L) or V106I/Y188L (with a potential contribution from L100I, E138K and Y181C). Characterization of the observed mutations by site-directed mutagenesis in the isogenic HXB2D background demonstrated that a minimum of two or more mutations were required for significant loss of susceptibility, with the exception of Y188L, which requires a two-nucleotide change. Patterns containing F227C or quadruple mutations selected by RO-0335 showed a low relative fitness value when compared to wild-type HXB2D.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Substituição de Aminoácidos/genética , Fármacos Anti-HIV/química , Linhagem Celular , Análise Mutacional de DNA , Humanos , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto , Inibidores da Transcriptase Reversa/química , Inoculações Seriadas
2.
J Nanosci Nanotechnol ; 1(4): 451-5, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12914087

RESUMO

CdTe nanocrystals were synthesized in aqueous solution using 1-thioglycerol and 2-mercaptoethanol as surface stabilizers. The nanocrystals were characterized by means of X-ray powder diffraction and UV-vis absorption measurements. The UV-vis absorption spectra exhibit two distinct transition lines. Comparison of the experimental measurements with the results of the empirical pseudopotential calculations of the CdTe nanocrystals showed that the lower energy absorption line can be assigned to the heavy-hole exciton transition, whereas the higher energy absorption line can be attributed to the light-hole exciton transition.


Assuntos
Compostos de Cádmio/química , Cristalização/métodos , Modelos Moleculares , Nanotecnologia/métodos , Telúrio/química , Compostos de Cádmio/síntese química , Compostos de Cádmio/isolamento & purificação , Simulação por Computador , Eletroquímica/métodos , Transferência de Energia , Conformação Molecular , Difração de Pó , Espectrofotometria , Telúrio/isolamento & purificação , Água/química
3.
Bioorg Med Chem ; 3(10): 1405-15, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8564408

RESUMO

Leukotriene A4 hydrolase is a zinc-containing enzyme which catalyzes the hydrolysis of LTA4 to LTB4, a proinflammatory mediator. The enzyme also exhibits an aminopeptidase activity. Due to its biological importance, it is of considerable interest to develop selective inhibitors of this enzyme. The design and synthesis of a number of potent beta-amino hydroxylamine and amino hydroxamic acid inhibitors are described here. It was found that having a free amine was essential for high activity. Hydroxylamines were found to be about an order of magnitude less potent than their analogous hydroxamic acids. Our investigation of amino hydroxamic acids as inhibitors of leukotriene A4 hydrolase has led to the development of hydroxamates 16 and 17, which are among the most potent inhibitors found to date. These, compounds were found to be competitive inhibitors with Ki values of 1.6 nM and 3.4 nM respectively, against the peptidase activity. Inhibitor 16 has an IC50 value of < or = 0.15 microM against the epoxide hydrolase activity and is also potent against the production of LTB4 by isolated polymorphonuclear leukocytes (PMNL) activated with ionophore A23187 (IC50 approximately 0.3 microM).


Assuntos
Inibidores Enzimáticos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Hidroxâmicos/síntese química , Sítios de Ligação/efeitos dos fármacos , Calcimicina/farmacologia , Quelantes/química , Quelantes/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/química , Granulócitos/efeitos dos fármacos , Granulócitos/enzimologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Ionóforos/farmacologia , Espectroscopia de Ressonância Magnética , Zinco/metabolismo
4.
Bioorg Med Chem ; 3(7): 969-95, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7582974

RESUMO

In an effort to better understand the favorable binding interactions between the reversible picomolar inhibitor 3-(4-benzyloxyphenyl)-2-(R)-amino-1- propanethiol (1) and leukotriene A4 (LTA4) hydrolase (EC 3.3.2.6), we prepared a number of derivatives of 1-L and other related structures, and assayed their inhibition of LTA4 hydrolase-catalyzed hydrolysis of L-alanine-p-nitroanilide. The inhibition data was analyzed using a weighted non-linear least-squares curve fitting computer program developed for this purpose to fit data derived under the non-Michaelis-Menten condition of [I]t < [E]t. The free thiol is necessary for sub-micromolar binding and the enzyme prefers the R enantiomer over the S enantiomer, in contrast to the stereoselectivity displayed towards bestatin, an inhibitor of somewhat similar structure. Substitution of acid moieties around the periphery of the benzyloxyphenyl portion of 1-L leads to substantially decreased binding, suggesting that this group resides within a large hydrophobic pocket when bound to the enzyme. Possible LTA4 binding modes in the active site of LTA4 hydrolase, including a possible direct role for the carboxylic acid of LTA4 in the enzyme-catalyzed hydrolysis of leukotriene A4, are discussed.


Assuntos
Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Propilaminas/química , Compostos de Sulfidrila/química , Gráficos por Computador , Software , Relação Estrutura-Atividade
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