Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

Delivery strategies of amphotericin B for invasive fungal infections

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.

Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds and had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed.

Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.

Manifestaciones bucales en pacientes con VIH/SIDA en el área del Policlínico Docente Playa. 2011 / Oral lesions in HIV/AIDS patients at "Docente Playa" Polyclinic. 2011

Introducción: las manifestaciones bucales en los pacientes con VIH/SIDA pueden constituir el signo inicial de infección por VIH. Estas pueden transcurrir sintomáticas o asintomáticas y pueden a su vez indicar progresión de la enfermedad. Objetivo: identificar la prevalencia de las principales manifestaciones bucales según la edad y el sexo y su relación con el consumo de antirretrovirales. Método: se realizó un estudio descriptivo de corte transversal en el área del Policlínico Docente Playa, entre el mes de enero de 2010 e igual periodo de 2011. El universo lo constituyeron 57 pacientes con diagnóstico de VIH/SIDA, que se presentaron con urgencias estomatológicas en la mencionada institución previo consentimiento informado. Los datos se procesaron con el paquete estadístico SPSS. Resultados: el 87.7% correspondió al sexo masculino y el 43.9 % con edades de 40 a 49 años. Entre las manifestaciones bucales se destacaron la enfermedad periodontal en el 57.9 %, el 22.8 % con la estomatitis aftosa recurrente (EAR). El 46.9 % de los pacientes, no consumían medicamentos antirretrovirales y el 53,1% sí lo consumían. Conclusión: las manifestaciones bucales mayormente tratadas fueron las relacionadas con la enfermedad periodontal y la estomatitis aftosa recurrente (EAR).

ABSTRACT Introduction: oral lesions in HIV/AIDS patients are sometimes the initial symptoms of VIH infection. They may occur in symptomatic or asymptomatic HIV infected persons. Objectives: identify sex, age and frequency of oral lesions in HIV patients and their relationship with antiretroviral consumption drugs. Method: a cross sectional, descriptive and observational study was made in order to identify frequency, age and sex of HIV patients with oral lesions and the relationship to antiretroviral drugs consumption.The sample included 57 HIV/AIDS adult patients who attended stomatological urgencies at "Docente playa" polyclinic during a year (Jan 2010, Jan 2011). Results: the 57,7 % of the sample were male. The age between 40 to 49 years old prevailed representing a 43,8 % of the total surveyed. Periodontal diseases prevailed with a 57,8 % meanwhile a 22,8 % had recurrent aphthous tomatitis.Finally, the 96,4% of the VIH patients surveyed had oral lesions. 53,1% of these patients took antiretroviral drugs. Conclusions: periodontal diseases and recurrent aphthous stomatitis prevailed among the oral lesions treated at the period studied.

Morbimortalidade de adolescentes com HIV/Aids em serviçode referência no sul do Brasil / Morbimortality of adolescents who have HIV/Aids in a reference centre in the south of Brazil

Com o avanço da epidemia da aids no Brasil, evidenciou-se uma tendência à juvenização do seu perfil epidemiológico, ou seja, a distribuiçãodos casos de aids na população de adolescentes. Objetivo: caracterizar a morbimortalidade de adolescentes com HIV/aids que foram atendidos no Hospital Universitário de Santa Maria (HUSM/RS/Brasil), no período de 1993 a 2011. Métodos: estudo descritivo, documental, retrospectivo, com abordagem quantitativa. Os prontuários do HUSM foram a fonte de informação de dados. A população do estudo foi de 45 adolescentes com HIV/aids, na faixa etáriade 13 a 19 anos, segundo critério etário estabelecido pelo Programa Nacional de DST/Aids do Brasil. Resultados: desta população, 60% eram meninas,48% de 13 a 14 anos, em 66,7% a transmissão foi vertical, 44,4% tiveram diagnóstico até os 5 anos de idade, 46,7% tiveram de quatro a seis consultas no último ano, 49% foram assíduos, 84,4% faziam uso de antirretrovirais, 92,2% com esquema duplo, 44,7% há mais de 9 anos, 60% já haviam tido doença oportunista, e 75,6%, internação hospitalar. Foram notificados dois óbitos. Conclusão: evidenciou-se a fragilidade clínica pelo comprometimentoimunológico e doenças oportunistas, pela necessidade de acompanhamento clínico, laboratorial e medicamentoso permanentes, pela demanda de adesão aotratamento e exposição a efeitos adversos, o que indica a necessidade de integralidade na atenção à saúde dos adolescentes, com o compromisso de atenderàs demandas específicas da condição sorológica e da fase de crescimento e desenvolvimento

The advancement of the aids epidemic in Brazil showed a youngest tendency with its epidemiological profile, in others words, the distributionof aids cases in adolescents. Objective: to characterize morbidity and mortality of adolescents with HIV/aids who were treated in the University Hospital of Santa Maria (UHSM/RS/Brazil), from 1993 to 2011. Methods: descriptive, documental, retrospective study with quantitative approach. The source of data information was patients'records at UHSM. Study population was of 45 adolescents with HIV/aids, aged 13 to 19, according age criteria established by Brazilian National STD/Aids Program. Results: from this population, 60% were girls, 48% aged 13-14 years old, in 66.7% infection was vertical,44.4% were diagnosed until 5 years old, 46.7% had four to six consults in the last year, 49% were assiduous, 84,4% were taking antiretroviral, 92,2% withdouble scheme, 44.7% were older than 9 years old, 60% already had opportunist illness, and 75.6%, were admitted in a hospital before. Two deaths were notified. Conclusion: it was evidenced clinical fragility through immunological compromise and opportunist illnesses, through need of permanent clinical,laboratorial and drug monitoring, for the demand of adherence to treatment and exposure to adverse effects, which indicates the need of integrality in healthcare to adolescents in commitment to answer serological condition and the growing and the development phase'specific demands.