Science and Medicine

Orally available cidofovir derivative active against smallpox

by Jane Bradbury

US researchers reported promising results on hexadecyloxypropyl-cidofovir (HDP-cidofovir), an oral drug active against smallpox, at the 15th International Conference on Antiviral Research (Prague, Czech Republic; March 17-21). "Cidofovir itself is active against smallpox but has to be given intravenously which limits its usefulness", says researcher Karl Hostetler (Veterans Affairs Medical Center and University of California, San Diego, CA, USA). "Provided it passes all the necessary toxicity and safety tests, HDP-cidofovir could be self-administered." And, he adds, "because it is also active against cytomegalovirus and herpes, varicella zoster, and Epstein Barr viruses, the agent might also be of use in more common diseases".

Smallpox was officially eradicated globally in December, 1979, but because of fears that smallpox might be used in bioterrorism, the US government is actively looking for smallpox antivirals. In an initial screen of existing compounds, John Huggins and colleagues (US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA), working at the US Centers for Disease Control and Prevention maximum containment laboratory (CDC, Atlanta, GA, USA), discovered that cidofovir, an intravenous drug licensed for use in cytomegaloviral infections, was active against smallpox. The US National Institute of Allergy and Infectious Diseases (NIAID) then turned to Hostetler. "My colleague John Beadle and I had been working for some time on designing derivatives of antivirals to make them orally available and, in 1999, NIAID asked us to apply this strategy to cidofovir", explains Hostetler.

Hostetler describes his strategy as a "Trojan horse" approach. "We have adapted cidofovir to look like a natural dietary phospholipid so it is taken up into the bloodstream and delivered to the tissues intact." Here, says Hostetler, the lipid part is cut off, cidofovir is activated by cellular enzymes, and viral replication is inhibited.

Unlike cidofovir, HDP-cidofovir is 93% orally available in mice. In addition, Hostetler found that HDP-cidofovir is 100-1000 fold more active than cidofovir against herpesvirus and cytomegalovirus in vitro. "We then sent the drug to John Huggins and Earl Kern [Universty of Alabama, Birmingham, AL, USA] to test it against pox viruses, including smallpox, in culture. Again, HDP-cidofovir was 100-200 fold more active than cidofovir." Finally, in a lethal mouse cowpox model, Huggins and colleagues found that five small doses of HDP-cidofovir prevented death.