Beyond Chicken Soup

DeepOcean

From: Scientific American www.sciam.com\2001\1101issue\1101haseltine.html Beyond Chicken Soup The antiviral era is upon us, with an array of virus-fighting drugs on the market and in development. Research into viral genomes is fueling much of this progress By William A. Haseltine Back in the mid-1980s, when scientists first learned that a virus caused a relentless new disease named AIDS, pharmacy shelves were loaded with drugs able to treat bacterial infections. For viral diseases, though, medicine had little to offer beyond chicken soup and a cluster of vaccines. The story is dramatically different today. Dozens of antiviral therapies, including several new vaccines, are available, and hundreds more are in development. If the 1950s were the golden age of antibiotics, we are now in the early years of the golden age of antivirals. This richness springs from various sources. Pharmaceutical companies would certainly point to the advent in the past 15 years of sophisticated techniques for discovering all manner of drugs. At the same time, frantic efforts to find lifesaving therapies for HIV, the cause of AIDS, have suggested creative ways to fight not only HIV but other viruses, too. A little-recognized but more important force has also been at work: viral genomics, which deciphers the sequence of "letters," or nucleic acids, in a virus's genetic "text." This sequence includes the letters in all the virus's genes, which form the blueprints for viral proteins; these proteins, in turn, serve as the structural elements and the working parts of the virus and thus control its behavior. With a full or even a partial genome sequence in hand, scientists can quickly learn many details of how a virus causes disease--and which stages of the process might be particularly vulnerable to attack. In 2001 the full genome of any virus can be sequenced within days, making it possible to spot that virus's weaknesses with unprecedented speed. The majority of antivirals on sale these days take aim at HIV, herpesviruses (responsible for a range of ills, from cold sores to encephalitis), and hepatitis B and C viruses (both of which can cause liver cancer). HIV and these forms of hepatitis will surely remain a main focus of investigation for some time; together they cause more than 250,000 cases of disease in the U.S. every year and millions in other countries. Biologists, however, are working aggressively to combat other viral illnesses as well. I cannot begin to describe all the classes of antivirals on the market and under study, but I do hope this article will offer a sense of the extraordinary advances that genomics and other sophisticated technologies have made possible in recent years. Drug-Search Strategies The earliest antivirals (mainly against herpes) were introduced in the 1960s and emerged from traditional drug-discovery methods. Viruses are structurally simple, essentially consisting of genes and perhaps some enzymes (biological catalysts) encased in a protein capsule and sometimes also in a lipid envelope. Because this design requires viruses to replicate inside cells, investigators infected cells, grew them in culture and exposed the cultures to chemicals that might plausibly inhibit viral activities known at the time. Chemicals that reduced the amount of virus in the culture were considered for in-depth investigation. Beyond being a rather hit-or-miss process, such screening left scientists with few clues to other viral activities worth attacking. This handicap hampered efforts to develop drugs that were more effective or had fewer side effects. Genomics has been a springboard for discovering fresh targets for attack and has thus opened the way to development of whole new classes of antiviral drugs. Most viral targets selected since the 1980s have been identified with the help of genomics, even though the term itself was only coined in the late 1980s, well after some of the currently available antiviral drugs were developed. After investigators decipher the sequence of code letters in a given virus, they can enlist computers to compare that sequence with those already identified in other organisms, including other viruses, and thereby learn how the sequence is segmented into genes. Strings of code letters that closely resemble known genes in other organisms are likely to constitute genes in the virus as well and to give rise to proteins that have similar structures. Having located a virus's genes, scientists can study the functions of the corresponding proteins and thus build a comprehensive picture of the molecular steps by which the virus of interest gains a foothold and thrives in the body. That picture, in turn, can highlight the proteins--and the domains within those proteins--that would be good to disable. In general, investigators favor targets whose disruption would impair viral activity most. They also like to focus on protein domains that bear little resemblance to those in humans, to avoid harming healthy cells and causing intolerable side effects. They take aim, too, at protein domains that are basically identical in all major strains of the virus, so that the drug will be useful against the broadest possible range of viral variants. After researchers identify a viral target, they can enlist various techniques to find drugs that are able to perturb it. Drug sleuths can, for example, take advantage of standard genetic engineering (introduced in the 1970s) to produce pure copies of a selected protein for use in drug development. They insert the corresponding gene into bacteria or other types of cells, which synthesize endless copies of the encoded protein. The resulting protein molecules can then form the basis of rapid screening tests: only substances that bind to them are pursued further. Alternatively, investigators might analyze the three- dimensional structure of a protein domain and then design drugs that bind tightly to that region. For instance, they might construct a compound that inhibits the active site of an enzyme crucial to viral reproduction. Drugmakers can also combine old-fashioned screening methods with the newer methods based on structures. Advanced approaches to drug discovery have generated ideas for thwarting viruses at all stages of their life cycles. Viral species vary in the fine details of their reproductive strategies. In general, though, the stages of viral replication include attachment to the cells of a host, release of viral genes into the cells' interiors, replication of all viral genes and proteins (with help from the cells' own protein-making machinery), joining of the components into hordes of viral particles, and escape of those particles to begin the cycle again in other cells. The ideal time to ambush a virus is in the earliest stage of an infection, before it has had time to spread throughout the body and cause symptoms. Vaccines prove their worth at that point, because they prime a person's immune system to specifically destroy a chosen disease-causing agent, or pathogen, almost as soon as it enters the body. Historically vaccines have achieved this priming by exposing a person to a killed or weakened version of the infectious agent that cannot make enough copies of itself to cause disease. So-called subunit vaccines are the most common alternative to these. They contain mere fragments of a pathogen; fragments alone have no way to produce an infection but, if selected carefully, can evoke a protective immune response. An early subunit vaccine, for hepatitis B, was made by isolating the virus from the plasma (the fluid