Neurodegenerative Disease

NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. Eriksen, J. L. et al. J. Clin. Invest. 112, 440–449 (2003).

Recent findings indicate that the apparent ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to protect against the development of Alzheimer's disease (AD) might be due to NSAID-induced reductions in the levels of the 42-amino-acid form of amyloid-β (Aβ42), which seems to have a key pathogenic role in AD. Building on this, Eriksen et al. provide data that indicate that the R isomer of the NSAID flurbiprofen reduces Aβ42 levels by targeting γ-secretase (the complex that produces Aβ42) and represents a good candidate for clinical testing, as it has low activity against cyclooxygenase, therefore reducing the risks of gastrointestinal side effects.

Antimalarial drugs

Artemisinins target the SERCA of Plasmodium falciparum. Eckstein-Ludwig, U. et al. Nature 424, 957–961 (2003)

Artemisinins are natural products that are important in the treatment of multidrug-resistant malaria, but they have to be administered frequently as they are quickly degraded in vivo. Artemisinins were thought to kill the malaria parasite through non-specific radical-mediated damage, but this paper provides strong evidence that they act by inhibiting a crucial parasite enzyme, the sarco/ endoplasmic reticulum Ca2+-ATPase — knowledge that should speed the development of longer-lasting artemisinin derivatives.

Viral disease

Molecular characterization, reactivation, and depletion of latent HIV. Brooks, D. G. et al. Immunity 19, 413–423 (2003).

Antiretroviral therapy is unable to eliminate HIV infection in a small, long-lived population of latently infected T cells, providing a source for renewed viral replication if therapy is stopped. Brooks et al. demonstrate a potential strategy to address this problem — activating the latently infected cells to make them susceptible to therapy and then targeting them with an anti-HIV immunotoxin — which depleted the bulk of the reservoir of latently infected T cells in mice.

Obesity

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Fu et al. Nature 425, 90–93 (2003).

Fu et al. identified the nuclear receptor PPAR-α as the molecular target of oleylethanolamide (OEA), a naturally occurring lipid that regulates eating behaviour. Their data indicate that PPAR-α activation not only mediates OEA-induced weight stabilization, as might be expected from the established metabolic roles of PPAR-α, but is also responsible for OEA-induced satiety.