Designing HIV entry inhibitors

In a search for more sophisticated molecules that block HIV-1 infection, Ferrer and colleagues report in the October issue of Nature Structural Biology the discovery of new molecules capable of targeting the fusogenic machinery of HIV. HIV enters cells by binding to target cell surface receptors and fusing with the cellular membrane, a process that requires the HIV membrane glycoproteins gp41 and gp120. To identify small organic inhibitors that block gp41 function, the authors screened a combinatorial library of 61,275 potential ligands. This library had an unusual feature: the monomers included 'non-natural' amino acids that could be linked to peptides by amide bonds. The best inhibitors identified contained small molecules covalently attached to peptides derived from the sequence of the gp41 outer-layer alpha helix. These 'hybrid' inhibitors are believed to bind the inner core of gp41 during an transient intermediate stage of fusion, to prevent contact with the target cell membrane. The molecules discovered in this screen may be superior to previously described natural inhibitory peptides because they are smaller, less susceptible to protease degradation, and easier to deliver to patients.

S ara M ariani

HIV Tat delivers

One of the chief limitations of many recent therapeutic strategies is the requirement for delivery of proteins across cell membranes or the blood–brain barrier. In the 3 September issue of Science, Dowdy and colleagues suggest the ability to overcome these obstructions through the use of HIV Tat protein, which can enter cells without using a cell surface receptor. Dowdy originally reported in the December 1998 issue of Nature Medicine that the 11-amino-acid protein transduction domain of Tat could be used to deliver functional proteins into cultured cells. His group has now taken this one step further–demonstrating that a β-galactosidase-Tat fusion protein, when injected into mice, permeates throughout the body. These findings are important in that β-galactosidase is a large molecule, and even though the fusion protein is injected as a denatured protein, the enzyme refolds to become biologically active in tissues including liver, kidney, lung, heart, spleen, and all regions of the brain. This will be a major step forward in the development of vaccine and protein therapies, especially those requiring central nervous system delivery, as previous agents designed to carry drugs across the blood-brain barrier were limited to very small, highly lipophilic peptides.

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Reason to keep an eye on ICSI

There is an ongoing debate about the safety of intracytoplasmic sperm injection (ICSI) and whether children conceived by this form of assisted reproductive technology have a higher rate of heritable defects (see Nature Medicine, April 1999). A study published in the 21 August issue of The Lancet suggests that infertile men who reproduce by ICSI may be passing dangerous tracts of trinucleotide repeats on to future generations. The authors of the study observed significantly longer tracts of the nucleotides CAG in the androgen receptor gene of men with the spermatogenesic defects azoospermia or oligosoospermia. Expansions of CAG repeats in the androgen receptor gene can cause spinal and bulbar muscular atrophy, also known as Kennedys disease, and CAG expansions in other genes are associated with several hereditary neurodegenerative diseases with similar clinical features. The authors also suggest that an increased number of androgen receptor gene CAG repeats may cause the spermatogenic defects in the patients included in this study. The androgen receptor gene is on the X chromosome, so male offspring will not inherit androgen receptor gene mutations, but female offspring will be carriers. Therefore, it may take several generations to observe the full genetic effects of reproduction by ICSI.

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A role for IL-1 receptor in mental retardation

Results of a study published in the September issue of Nature Genetics indicate that a member of the interleukin-1 (IL-1) receptor family is responsible for mental retardation. X-linked genetic defects are believed to cause cognitive impairments in approximately half of all severely mentally retarded people, but so far, only four X-linked mental retardation (MRX) genes have been identified. Analysis of the MRX locus in families afflicted with this disorder showed large deletions in a previously unidentified gene, which the authors called IL1RAPL because of its high levels of homology to the IL-1/Toll receptor family. The mouse homolog, Il1rapl, is expressed in regions of the brain associated with memory and learning, such as the hippocampal formation and dentate gyrus. Given previous reports that IL-1 administration affects hippocampal activity, it seems that the IL-1 signaling cascade may be important in the central nervous system as well as the immune system.

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MRI makes the connection

Recent developments in magnetic resonance imaging (MRI) will allow for noninvasive tracking of neuronal connections between functioning regions of the brain. In the 31 August issue of the Proceedings of the National Academy of Sciences Conturo, et al. reported a new system of tracking neuronal fibers in living humans by MRI. MRI has the unique ability to characterize water diffusion in tissue. Conturo et al. took advantage of the fact that brain water preferentially diffuses in the direction of white matter fibers, and designed an MRI method to reconstruct fiber trajectories throughout the brain. By combining this technique with functional MRI, the researchers are now able to determine neuronal pathways that connect different functional brain regions. This finding is a major advance for neuroscientists, as these anatomical connections were previously determined by clinical–pathological correlations based on demyelination patterns in deceased humans, or through injection of fluorescent tracer molecules into animals.

This technique will allow for a more detailed study of the organization of brain systems in normal and abnormal living humans.

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