WHAT better way to kill a virus than to mutate it to death, relentlessly sabotaging its genes until it can no longer survive? If everything goes to plan, that鈥檚 the fate in store for HIV and other killers including Ebola and West Nile virus.
The tool for the job is a new class of HIV drug called a 鈥渟tealth nucleoside鈥�. The first trial of the therapy in animals began last week after a series of successful test-tube studies.
鈥淲e鈥檙e pushing the virus over the edge,鈥� says Richard Daifuku head of Koronis Pharmaceuticals, a biotechnology firm in Redmond, Washington state, which is developing stealth nucleosides.
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鈥淚f mutations get above a critical level, then the virus can鈥檛 replicate any more,鈥� he said last week when he presented the company鈥檚 latest findings at the BioPartnering Europe conference in London.
Koronis is confident that because of the way the drug works, HIV will be unlikely to develop resistance. This is because the drug inflicts extensive damage to the genetic material of the virus, damage that is random and widespread enough to cripple it beyond repair (New 杏吧原创, 28 October 2000, p 34). The hope is that a couple of doses of the new drug per day could replace the complex drug regimes now used against HIV to keep resistance at bay, which can involve taking numerous pills several times a day.
Daifuku鈥檚 stealth nucleoside, called SN1212, is designed so that HIV mistakes it for uracil 鈥� one of the four building blocks of RNA 鈥� and incorporates it into its RNA. The adulterated RNA snarls up the complementary DNA copy that the virus makes from it. Wherever SN1212 has stolen in, mistakes can appear in the DNA copy (see Diagram).
Normally, an adenine building block is added to the DNA copy of the viral sequence to match every uracil in the original RNA strand. But SN1212 is designed to bind to two other building blocks, namely cytosine or guanine, as well as the usual adenine. The result is that the viral genome inexorably fills up with mistakes.
鈥淲e mutate across all viral genes,鈥� says Daifuku. This contrasts with most existing anti-HIV drugs such as lamivudine, which also disrupt viral replication but do so by stopping further nucleosides from being added. The trouble with this approach is that, eventually, some viral variants become resistant.
Daifuku acknowledges that he can鈥檛 rule out the possibility that some of the mutations will benefit the virus. But lab experiments on infected cells suggest that for each beneficial mutation there will be countless others that spell doom for HIV.
The stealth nucleosides should affect only viral genetic material, not ours. That鈥檚 because our cellular repair enzymes 鈥� which viruses don鈥檛 have 鈥� can snip out SN1212 whenever it is mistakenly added to our DNA. 鈥淰iruses don鈥檛 have our proof-reading mechanisms, which repair the errors,鈥� says Daifuku.
He admits, however, that some mistakes might creep into patients鈥� DNA, leading to a theoretical increase in the risk of cancer. But he is confident that the drug is safe, for two reasons. It鈥檚 a breakdown product of a medicine already in use (which he won鈥檛 name). And recent research suggests that Ribavirin, an existing drug for hepatitis C sold by Schering, works by a similar mechanism to SN1212. Patients taking these drugs are not thought to have an increased risk of cancer.