Antiviral drugs: Blocking the route to infection

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A promising approach to improve the pharmacological properties of a natural protein that blocks HIV entry could also be applicable to other therapeutic proteins.

A promising approach to developing agents that can prevent HIV transmission is described in a recent report in Proceedings of the National Academy of Sciences. Furthermore, the medicinal chemistry strategy used by Offord and co-workers to improve the pharmacological properties of a natural protein that blocks HIV entry could also be applicable to other therapeutic proteins.

The entry of HIV into target cells involves the CD4 protein, as well as the CC-chemokine receptor 5 (CCR5), which is especially important in the early stages of the disease. Natural ligands of CCR5 — such as RANTES, a small human protein of the chemokine family — can block the entry of HIV strains that require CCR5 to enter the target cells.

Optimizing such proteins to make them more potent inhibitors of HIV entry could lead to agents that effectively prevent HIV transmission. Small proteins have traditionally been modified using mutagenesis, but this approach is limited to natural amino acids; now, however, techniques are available for the rapid chemical synthesis of large numbers of analogues of small natural proteins, which allows non-natural amino acids to be incorporated that might improve the therapeutic properties of the analogues.

Previously, Offord and co-workers synthesized a RANTES analogue — AOP-RANTES — that was more effective at blocking HIV entry into target cells than natural RANTES. In AOP-RANTES, a serine residue was replaced with the non-natural amino acid aminooxypentane oxime on the amino terminus to increase its hydrophobicity. In the current study, the authors systematically determined the structure–activity relationships of analogues of AOP-RANTES, which led to the generation of several more potent inhibitors of HIV in mice. The analogues were further optimized by replacing the amino acids at the two adjacent positions to the original amino acid that was modified. One derivative of AOP-RANTES, termed PSC-RANTES, was 50 times more potent than the starting molecule.

These RANTES analogues are thought to be successful at inhibiting HIV entry into target cells because they trigger the intracellular sequestration of CCR5. Offord and co-workers reported a correlation between potency and capacity to induce CCR5 sequestration.

However, contrary to earlier predictions that this capacity relates to increased affinity for the receptor, there was no correlation between affinity and potency. Future studies might shed light on the mechanism by which these modifications lead to intracellular sequestration of CCR5, and could lead to the development of clinically effective inhibitors of HIV transmission.

Alison Rowan

References

Hartley, O. et al. Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc. Natl Acad. Sci. USA 101, 16460–16465 (2004) | Article | PubMed |
Lederman, M. M. et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306, 485–487 (2004) | Article | PubMed |