Bioconjugate Chemistry Links A Number Of Fields

Landmark Papers Although the term "bioconjugate chemistry" was coined relatively recently, researchers increasingly have been exploring the techniques and applications of this field, particularly during the past 10 years. Simply put, bioconjugate chemistry involves the joining through chemical or biological means of two molecules that exhibit different biological activities to form a new compound with specific biochemical properties. As scientists learn more and more about the roles of specific molecules in the human body and discover the progression of various diseases, they turn to bioconjugate chemistry to develop useful compounds, such as new diagnostic tools and target-specific drugs. The Scientist spoke to Claude F. Meares of the department of biochemistry at the University of California, Davis, and editor of a new journal, Bioconjugate Chemistry (The Scientist, Association Briefs, March 5, 1990, page 9), to ask about recent trends in this wide-ranging field. The accompanying table lists key articles in bioconjugate chemistry, which were given to The Scientist by Meares. Meares considers these papers landmark studies that opened the door for further research. The papers are ranked by the number of citations each received from its year of publication through 1989. These data were derived from the Philadelphia-based Institute for Scientific Information's Science Citation Index. The 10 articles, which have appeared in a variety of journals, cover many topics, including conjugates of antibodies, chelating agents, nucleic acids, and liposomes. The authors, who hail from private laboratories, industry, and academia, work in disciplines as varied as the topics. The backgrounds of the authors whose papers appear in the first issue of Bioconjugate Chemistry are also richly diverse. Researchers in chemistry, food science, pharmacology, chemical engineering, biochemistry, microbiology, chemical engineering, and even bioacoustics are exploring aspects of bioconjugate chemistry. Scientists have conjugated various compounds with each other or other molecular substances, such as chelates or antigens, in an attempt to produce drugs for cancer (The Scientist, April 2, 1990, page 20) and viral infections, radionuclides, DNA probes (for diagnostics), inhibitors, enzymes, and so on. Bioconjugate chemistry can also be used in DNA sequencing and analysis, the manufacturing of synthetic vaccines and enzymes, separartion science, analytical techniques, and protein modification. "It's definitely a multidisciplinarian field," says Paul S. Miller, a biochemist at Johns Hopkins University in Baltimore and associate editor of the new journal. Miller and his colleagues are currently applying the principles of bioconjugate chemistry to nucleic acid analogs in the hope of developing antiviral drugs. Miller adds that these same antisense oligonucleotides can "be used for chemotherapeutic agents down the road, when the targets [cancer cells] are better understood. When we know more about cell transformation and tumor progression, we can take advantage of that information." Despite the multidisciplinary nature of this field, Miller says, various scientists really don't have "much trouble understanding each other." The real problem, he says, is finding out who's doing what research. Articles on bioconjugate chemistry have traditionally shown up in a number of diverse journals. Some of these journals, such as Journal of Immunology and Cancer Research, normally have rather specific audiences. The challenge, then, for researchers in bioconjugate chemistry is to first find the information and then relate it to their own individual research projects. "Similar techniques," says Miller, "can be applied to different problems." An example of the information that scientists can share is the various coupling techniques used to link the different molecules together. A researcher looking for a way to combine a toxin with a monoclonal antibody as a means of killing cancer cells, for example, may take advantage of a linking technique developed by another scientist seeking to come up with an accurate diagnostic tool. Deciding which compounds to link to one another is the initial step in bioconjugate chemistry. This step, says Miller, is usually a combination of preliminary computer modeling and good old-fashioned trial and error. Which of these two techniques a researcher leans toward depends, says Miller, on "the type of conjugate and what you want to do with it." Scientists use computer modeling, for example, when developing conjugates of nucleic acids and proteins. "We know their [proteins and nucleic acids'] properties," says Miller, so the scientists rely on models to check whether or not "these properties will combine to give something useful." Linking one molecule to another, however, isn't as simple as linking together Tinkertoys. "The chemistry can be tricky," says Miller. The challenge, he says, "is finding a linking molecule that reacts with molecule A and molecule B without destroying their properties or modifying them in any way." Different linking compounds can affect the efficacy of, say, an anticancer or antiviral drug. For example, an article in the first issue of Bioconjugate Chemistry (V. Ghetie, et al., 1:24-31, 1990), explores the effects three different linking agents have on conjugates of recombinant human CD4 (rCD4) and the toxic deglycosylated ricin A chain. Conjugates of these two compounds are potential therapeutics against the human immunodeficiency virus (HIV). The rCD4 component of these conjugates binds to the HIV-infected cells by reacting with the glycoprotein that coats the virus. The toxic ricin A chain kills the cells by prohibiting protein synthesis. For their study, the researchers examined the structure and cytotoxicity of each of the three rCD4-ricin A chain conjugates. They also analyzed the pharmocokinetic properties, tissue localization ability, and toxicity (in mice) of each prepared molecule. Another hurdle that researchers in bioconjugate chemistry must jump is that of reactivity. Miller says that certain molecules, such as proteins and nucleic acids, "have a number of different functional groups that are reactive." The trick here is to bind the other molecule to one specific reactive site without triggering the others. "We want to achieve a selectivity in an action," explains Miller. "We want very selective agents. This is quite important in chemotherapeutics and other medicinals." Scientists developing bioconju-gates for use as therapeutics in cancer and viral research must come up with a molecule that will zero in on a specific type of cell or virus. Accurate targeting, however, is only part of the process. Once at the target site, the conjugate must be able to release the drug or toxin. Researchers also concern themselves with producing a therapeutic bioconjugate that will do more good than harm. The trick, then, is to produce a potent molecule capable of attacking very specific targets. Perhaps one of the greatest challenges bioconjugate chemists will face in the future, says Miller, is successfully purifying any conjugated products that will have therapeutic applications. "Most of the people are working on very small-scale, lab-scale operations," he says. "The challenge will be to make large quantities." In addition to its utility in the production of potentially therapeutic agents, Miller believes, bioconju-gate chemistry will play a key role in the development of improved diagnostics for the early detection of a variety of diseases. Giving this field a name and its own journal may help quicken the pace at which significant breakthroughs are made.

Bioconjugate Chemistry Links A Number Of Fields

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