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Small nonpeptide compounds inhibit protein interactions
Transcript of Small nonpeptide compounds inhibit protein interactions
Small nonpeptide compounds inhibit protein interactions Researchers in Philadelphia have combined structure-based drug design with computer-based screening of a large database of small molecules to identify several nonpeptide compounds that inhibit immune activation of Τ cells.
The findings have fundamental significance in that small nonpeptide molecules that inhibit interactions between large proteins, such as those in the immune system, have been identified only rarely. But they also have practical importance because the compounds identified in the study are potential leads for the development of treatments for transplant rejection, autoimmune diseases, and other immunological disorders.
The work was carried out by biochemistry and molecular pharmacology professor Ziwei Huang and coworkers Song Li, Jimin Gao, Takashi Satoh, Thea M. Friedman, Andrea E. Edling, Ute Koch, Swati Choksi, Xiaobing Han, and Robert Korngold at Kimmel Cancer Institute of Jefferson Medical College, Philadelphia [Proc. Natl. Acad Set. USA, 94, 73 (1997)].
The researchers used DOCK—a program developed by Irwin D. Kuntz and coworkers at the department of pharmaceutical chemistry of the University of California, San Francisco (UCSF)—to search a large compound library for li-gands that could fit into a pocket of the CD4 receptor on T-cell surfaces. In previous studies, Huang and coworkers have proposed that this CD4 surface pocket is the site involved in complex formation between CD4 and the major histocompatibility complex (MHC) class Π molecule. MHC class Π is a large protein on the surface of antigen-presenting cells-trie cells that process antigens and present them to the immune system.
CD4 binding to MHC class II is part of the body's normal immune response to antigens. However, this interaction can also trigger adverse immune responses, such as those that occur in transplant rejection and autoimmune disease.
Anti-CD4 monoclonal antibodies that block T-cell activation have been developed as potential treatments for immune system disorders. However, the inherent immunogenicity of such antibodies has "reduced their value as an effective treatment," Huang and coworkers write. In
the current study, Huang's group sought small organic nonpeptide compounds that would likely be nonimmunogenic and orally active as well.
Huang and coworkers used DOCK to evaluate the quality of fit of ligands in the CD4 pocket based on shape complementarity and charge interactions. The program evaluated every compound in a commercially available database of about 150,000 small organic molecules. The researchers used empirical rules and structural and chemical intuition to select the 41 best candidates from among the compounds identified by DOCK. Those compounds were then tested for biological activity, and three of them emerged as the most promising leads.
Peptide inhibitors of large protein-protein interactions have been developed,
CD4 surface pocket bound by organic Inhibitor (shown In pink at upper right).
Reprinted with permission from Proc. Natl. Acad. Set. USA, 94, 73 (1997), copyright 1997 National Academy of Sciences, USA.
but are not common. And nonpeptide inhibitors such as those identified in the current study are even more rare. This is "an area which remains largely unexplored for drug design," says Huang.
A small cyclic heptapeptide was earlier designed and synthesized, in a yet-unpublished study, by Huang's group in collaboration with Jefferson Medical College groups led by immunologist Korngold and NMR spectroscopist Markus W. Germann. Like the organic inhibitors identified in the current study, the heptapeptide blocks the stable association between CD4 and MHC class II proteins by targeting the same CD4 surface pocket.
The heptapeptide has been shown to be highly effective in animal models for human multiple sclerosis, organ transplant rejection, and graft-versus-host disease (which often occurs after bone marrow transplantation). Phase I clinical trials are planned to start soon to evaluate its side effects and activity in bone marrow transplant and multiple sclerosis patients. Huang says he hopes initial trials on the heptapeptide will provide the groundwork for future trials of organic compounds developed from leads identified in the current study.
Asked to comment on the Huang group's development of nonpeptide inhibitors, Fred E. Cohen, UCSF professor of pharmaceutical chemistry, says, "It is a nice piece of work. The challenge will be if these leads can be 'analoged' into more potent compounds. The molecules [Huang] identifies are quasi-druglike, and several look like they could be analoged to build a structure-activity relationship." Huang was formerly a postdoctoral fellow in Cohen's group and that of UCSF neurology and biochemistry professor Stanley B. Prusiner.
Biochemist James A. Wells of the department of protein engineering at Gen-entech Inc., South San Francisco, says, "The experiments are impressive in that compounds selected straight from DOCK, without further medicinal chemistry, were found to have potentially useful pharmacological properties." However, says Wells, "The compounds bind weakly and the authors have not confirmed that they bind to the designated cavity on CD4. There is clearly much more to be done here, but it is a tantalizing result and it will likely increase the interest in DOCK as a screening tool for identification of lead molecules."
Huang says he and his coworkers "agree that the potency of these compounds needs to be further improved. In fact, in recent preliminary studies subsequent to the PNAS work, we have already found modified analogs of these initial compounds that are active in much lower concentrations."
Huang adds that his group's results "have shown that these compounds appear to target specifically the CD4-MHC class Π complex. More studies will be carried out to examine whether there are additional targets, and, if so, to increase the specificity of the organic inhibitors. Another important challenge will be to extend this approach to other protein-protein interactions."
Stu Borman
JANUARY 13, 1997 C&EN 27