We used a novel rational design approach in the development of novel immunomodulatory peptides, in particular RDP58, with at least two primary biological activities, inhibition of TNF production and upregulation of heme oxygenase-1 (HO-1) activity. The design strategy used a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories to identify potential drug candidates. The process was initiated using a panel of 19 lead molecules derived from a functionallyimportant region of HLA I, on the premise that the peptides might modulate immune responses by blocking HLA / T lymphocyte interactions. Each of these 19 peptides was tested in vivo for potential cardiac allograft protection in a mouse model. Outcome of graft survival was the primary data available to describe nine of the peptides as active and ten as inactive. A virtual combinatorial library of 279,936 peptides was then generated, based on physical properties associated with efficacy in the original learning set of 19 peptides - in particular, the distribution of lipophilic residues. The library was screened using descriptors that fell into 2 categories: static (physico-chemical) and dynamic (conformational). The screenings identified 5 peptides with theoretic potential efficacy. These were synthesized and tested for activity in vitro and in vivo. Besides prolonging graft survival in rodents, RDP58 was found to inhibit TNF and increase HO-1 activity, these biological activities were tested exhaustively in various in vivo disease models. RDP58 demonstrated convincing potential to alleviate disease symptoms in many of the experimental diseases.