Eddy Arnold
	Professor Chemistry and Chemical Biology Rutgers, The State University of New Jersey Member Cancer Institute of New Jersey Ph.D., 1982, Cornell University Tel:  [732] 235-5323 Fax: [732] 235-5788 arnold@cabm.rutgers.edu Arnold Lab Website

HIV, AIDS, drugs, vaccines, crystallography, structural biology.

Drs. Eddy and Gail Ferstandig Arnold and their colleagues are working to develop and apply structure-based drug and vaccine designs for the treatment and prevention of serious human diseases. In pursuit of these goals, their laboratory takes advantage of cutting-edge research tools, including X-ray crystallography, molecular biology, virology, protein biochemistry, and macromolecular engineering.

The approaches being developed in the Arnold laboratory are broadly applicable to a wide array of human health problems, ranging from infectious diseases to cancer and diseases caused by hereditary genetic defects. Much of the Arnold lab’s research effort to date has focused on the development of drugs and vaccines for the treatment of AIDS. Examples of the results of these studies include: 1) collaborative development of potential drugs for the treatment of AIDS, some of which may be more effective than treatments in current use; and 2) production of AIDS vaccine candidates that have elicited protective immune responses against HIV.

Dr. Arnold studies reverse transcriptase (RT), which is an essential component of the AIDS virus and the target of many of the most widely used anti-AIDS drugs. Using the techniques of X-ray crystallography, his team has solved the three-dimensional structures of HIV-1 RT in complex with antiviral drugs and pieces of the HIV genome. These studies have illuminated the working of an intricate and fascinating biological machine in atom-by-atom detail and have yielded numerous novel insights into polymerase structure-function relationships, detailed mechanisms of drug resistance, and structure-based design of RT inhibitors. Synthesis of the information being developed has lead to the development of inhibitors that show great promise as potential treatments for AIDS.

Another major project in his laboratory, co-directed by Dr. Gail Ferstandig Arnold, consists of engineering of a human common cold virus, rhinovirus, to display appropriate segments from more dangerous pathogens for the purpose of developing vaccines against these pathogens. This work involves generating large numbers of chimeric human rhinoviruses using a technique called random systematic mutagenesis. With this method, the foreign sequences are linked to the HRV sequences via adapters of randomized sequences and lengths, leading to a large array of presentations. Large sets of such viruses are generated and selected to optimize the isolation of vaccine candidates with the most effectively reconstructed foreign segments. Constructs have been made that elicit antibodies (in guinea pigs) capable of potently neutralizing the AIDS virus in cell culture. His team is also analyzing the structures of some of the engineered viruses using X-ray crystallography, with the long-term objectives of determining three-dimensional correlates of immunogenicity and developing a structural basis for design of more effective human vaccines.

The Arnold group will continue to study medically important problems using basic scientific tools and approaches. In addition to potentially developing novel vaccines and chemotherapeutic agents, the laboratory aims to gain greater insights into the basic molecular processes of living systems.

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that successfully inhibit the wild type AIDS virus reverse transcriptase (RT) and clinically important drug-resistant variants.HIV evolves rapidly, undergoing extensive genetic variation. The evolution of drug resistance can be enhanced by drug selection pressure. The Janssen diaryltriazine (DATA) and diarylpyrimidine (DAPY) NNRTI inhibitors that are broadly effective against drug-resistant mutants of HIV-1 reverse transcriptase (RT) are shown bound to wild type and NNRTI resistant RTs (from work by scientists at the Janssen Center for Molecular Design, Janssen Pharmaceutica, Tibotec, NCI-Frederick, and CABM/Rutgers). These structures illustrate the importance of conformational adaptability in overcoming NNRTI resistance: R120393, TMC120-R147681 (dapivirine), and R185545 are bound to wild type HIV-1 RT and TMC125-R165335 (etravirine) is bound to an NNRTI-resistant RT mutant, Lys103Asn. The electrostatic potential surfaces of the NNIBP were calculated using the program GRASP; selected pocket residues were omitted to permit a clear view into the binding site. The compactness and conformational flexibility of the inhibitors permit them to “wiggle” and “jiggle” in response to changes in the structure and conformation of the binding pocket caused by drug-resistance mutations. This allows these inhibitors to inhibit mutant RTs that cause treatment failure with the NNRTIs currently approved for human use. From Das et al., J. Med. Chem. 47:2550-2560 (2004).

Selected Publications1