North Jersey Section
American Chemical Society

Danho Receives the 2009 Lifetime Achievement Award

Waleed_Danho-largeDr. Waleed Danho of Hoffmann-La Roche has a well deserved world-wide reputation as a leader and innovator in the field of peptide chemistry and the application of peptide chemistry to pharmaceutical discovery. Within Roche, he leads a peptide synthesis group that serves as a center of excellence for the entire global Roche organization. His style is characterized by openness, honesty, and a willingness to take the time to listen to others seeking advice. His drive and enthusiasm for science and success are exemplary and amazingly, seem to intensify as his career progresses. He serves as a role model for medicinal chemists and has expanded his influence greatly through his mentorship of younger chemists.

Waleed completed his Ph.D. degree in the laboratories of Prof. H. Zhan at the RWTH University of Aachen in Germany in 1967. During his graduate career, he developed a new synthesis of the A- chain of insulin leading to the first crystalline semi-synthetic insulin. After a postdoctoral fellowship at the University of California, San Francisco, with Professor C. H. Li on the synthesis of human growth hormone, he joined the faculty of the University of Baghdad, College of Medicine as an assistant professor of Biochemistry. His research on pancreatic and pituitary hormones of camels led to the critical discovery that lipotropin is a pro-hormone of endorphin.

In 1976 he returned to the University of Aachen, as a group leader in the Department of Insulin Research to continue his ground breaking work on the synthesis of insulin. His efforts on the synthesis of pro-insulin led to the preparation of a 45-amino acid fragment of pro-insulin and represented the largest fragment synthesized at that time by solution phase peptide synthesis. His research group went on to establish a structure-activity-relationship for insulin in an attempt to discover the core pharmacophore as documented in numerous publications.

In 1980 Waleed joined Hoffmann-La Roche Inc. as a Research Group Chief in the Chemical Research Department. Since that time he has risen to the rank of Distinguished Research Leader. His Roche career has been marked by a focus on peptides as drugs as well as tools for biological proof of concept. Waleed’s drive and ability to cultivate strong and extensive collaborations with medicinal and structural chemists have been critical to his success and ability to achieve his goals. The scope of these activities is documented in over 200 publications, 16 patents and a number of presentations at national and international peptide symposia. Some of the key contributions to Roche and peptide chemistry are highlighted in the paragraphs below.

Waleed’s early work at Roche involved the isolation, characterization and synthesis of thymic hormones in particular thymosin alpha-1. This work led to the discovery that thymosin alpha-1exists as a precursor and the hormone itself is a “by-product” or artifact of the purification step. The discovery led to the timely termination of the project at Roche. In the beginning of 1983 with advent of the “genetic revolution”, peptides became powerful tools for the quest for protein therapeutics. Waleed and his team led a number of efforts in the generation of antibodies and active site determination for proteins of therapeutic interest such as IL-1, Il-2 and Ig-E. This body of work was achieved through the synthesis of large numbers of linear and conformationally constrained peptides as “protein mimics” and represented the first step in the design of small molecule peptide mimics as drugs.

In 1985 Waleed in collaboration with Medicinal and Structural chemists co-led an effort to effectively develop peptides mimetics as small molecules drugs. The satiety peptide Cholecystokinin (CCK-7) was chosen as the target. Waleed systematically investigated the contribution of each of the amino acids as well as the conformational requirement of each of the side chains of the amino acids by synthesizing linear and cyclic peptides of CCK-7 leading to the to design of potent cyclic peptide mimetics. He also carried out key studies that led to the discovery of small molecule antagonists of IL-2 and the IL-2 receptor. Taken together, these efforts clearly demonstrated the complexity and challenges associated with using peptide and protein structures as the starting point for small molecule design and provided important guidance for future endeavors.

From 1994 to 1996 Waleed joined the anti-sense research group and was intimately involved in developing strategies for the automated ligation of peptide nucleic acids (PNA) which led to a Roche patented anti-sense technologies platform.

In 1996 Waleed assumed the leadership of a peptide metanocortin-4 (MC-4) receptor agonist program for the treatment of obesity. Waleed’s group embarked on establishing the structure-activity-relationship of MC-4 receptor agonists through conformational analysis and synthesis of linear and cyclic analogues. This led to the discovery of a highly specific and potent cyclic peptide MC-4 receptor agonist, as a candidate an anti-obesity agent. During the same period, it was recognized that the melanocortins, specifically the MC-4 subtype have an effect on erectile function. Under Waleed’s leadership an opportunistic program was initiated to identify and develop an MC-4 agonist for the treatment of male erectile dysfunction, and rapidly led to the discovery of a potent and selective peptide that has entered Phase 2 clinical trials.

Through his pioneering work on the melanocortins, and other GPCR ligands, Waleed developed a strategy to determine the chemical tractability of large peptide ligand GPCR’s as targets. More recently, Waleed was involved in the synthesis and design of peptide related to obesity and diabetes, in particular peptide YY. This led to the discovery of truncated, highly selective PYY3-36 (Y2R) agonists as well as strategies for their delivery and extending their duration of action.

Waleed’s scientific career has been marked by this unquenchable thirst for success. His enthusiasm and positive thinking is contagious and has been a great asset for the younger chemists who often seek him as an advisor, mentor, and coach. He is a deep and broad thinker and a most honest yet strongly optimistic debater, with an endless love for science. In addition to outstanding synthetic and analytical skills, he has an unmatched sense of structure and conformation concerning cyclic peptides; computer modeling usually confirms his design and predictions. His academic peers rank him among the world leaders of drug-discovery oriented peptide research. Thus his visibility is highly international and extends over both academia and the pharmaceutical industry.

The award will be presented to Dr. Danho at the NJ ACS annual award dinner on May 28 at Fairleigh Dickinson University.

Lee Babiss
Francois Diederich
Nader Fotouhi
Richard Houghten
Tomi Sawyer
Jefferson Tilley