Daniel H. Rich

Daniel H. Rich pioneered the design of peptide-based enzyme inhibitors through transition-state analog strategies, establishing fundamental principles for targeting aspartic proteases that would later guide development of HIV protease inhibitors and other therapeutic agents. His work on pepstatin analogs and cyclosporine chemistry demonstrated how conformational understanding enables rational inhibitor design.

Rich joined the School of Pharmacy at the University of Wisconsin-Madison, where he developed statine-containing inhibitors of aspartic proteases. His studies of pepstatin, the natural microbial inhibitor of pepsin and renin, revealed that the unusual amino acid statine mimics the tetrahedral transition state of peptide hydrolysis. This mechanistic insight led to systematic synthesis of pepstatin analogs with modifications at each subsite, enabling structure-activity relationships that informed subsequent drug design efforts against renin and HIV protease.

His research extended to cyclic peptides with immunosuppressive activity. Rich synthesized the unusual amino acid MeBmt found in cyclosporine and prepared analogs to explore how this cyclic undecapeptide achieves immunosuppression. His studies of cyclosporine conformation and cyclophilin binding contributed to understanding of this clinically important immunosuppressant.

Rich developed practical synthetic methods including dehydrosulfenylation for preparing dehydroamino acids, selective cleavage strategies for protected peptides, and solid-phase approaches to conformationally constrained inhibitors. His perspective article on designing peptidomimetics for the 21st century synthesized decades of experience into principles for targeting conformational ensembles of flexible enzymes. This work laid conceptual foundations for peptidomimetic drug design that continue to influence medicinal chemistry.