By David N. Leff

Mother Nature has gone and done it again. Having generated a bulky molecule, erythropoietin (EPO), which stimulates red blood cells to replicate, she also created a small, slender peptide that performs the selfsame job -- as molecular biologists discovered a year ago. (see BioWorld Today, July 26, 1996, p. 1.)

Now they have come up with a similar small peptide for a similar massive molecule, thrombopoietin (TPO).

Neither EPO nor TPO bears the slightest molecular or genomic relationship to its peptidic mimic. As with EPO, so with TPO, the novel act-alike little peptides are generating considerable interest in the drug-discovery echelons of the pharmaceutical industry.

This newest small molecule to hit their radar screens reached public attention earlier this month, via the June 13, 1997, issue of Science. It took the form of a paper titled: "Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine."

Thrombopoietin is a cytokine that signals cells when it's time to promote the growth of bone marrow precursors that make platelets. That time comes when thrombocytopenia sets in. This sudden drop in the bloodstream's cargo of platelets is a frequent and life-threatening side effect of cancer chemotherapy. (See BioWorld Today, March 1, 1997, p. 1.)

The toll that cancer chemotherapy takes on platelet levels is dose-limiting, with consequent diminution of anti-tumor efficacy.

The Science paper's senior author is William Dower, of the Affymax Research Institute, in Palo Alto, Calif. He told BioWorld Today: "We found this TPO-equivalent peptide the same way we found the one for EPO last summer, by screening recombinant peptide libraries. We found one high-affinity lead peptide, a weak agonist, with ability to activate the TPO receptor."

That determination led the Affymax team to recognize the peptide's typical mechanism -- dimerization. "This monomeric carboxy terminal linkage to a lysine branch," Dower said, "increased its potency 4,000-fold, the same as the natural 332-amino-acid recombinant human cytokine.

"It probably activates the TPO receptor," he suggested, "by inducing it to dimerize."

For preclinical testing of their putative platelet generator, Affymax enlisted the Glaxo Wellcome Research Institute, in Research Triangle Park, N.C.

David Bacchanari, who heads cancer biology at Glaxo, told BioWorld Today: "We're collaborating with Affymax, who are the experts in this whole technology of designing smaller molecules. We measured their TPO peptides, megakaryocyte maturation and preclinical efficacy in mice, as well as planning clinical studies for chemical or bone marrow toxicity." (Megakaryocytes are the giant cells in bone marrow that give rise to platelets on demand.)

"In those mice," Bacchanari went on, "a high dose of peptide was able to stimulate megakaryocytes in bone marrow and spleen, and raised platelet counts by 80 percent compared to control animals. The compounds had the same physical response," he added, "as the recombinant TPO protein has in vivo."

He offered no explanation as to "why Mother Nature second-guessed herself" by making both the heavy EPO and TPO proteins, and their light peptide counterparts. "It probably represented the evolution of proteins as life evolved" toward more efficient molecules, he surmised.

Bacchanari observed that besides having analyzed the EPO and TPO peptides, Affymax also is working on "the third and last of the three major blood types, the interleukin-1 receptor."

Dower volunteered: "We licensed those EPO peptides to Johnson & Johnson, which continues to study them, but we are not privy to their development plans."

Bacchanari concluded that "the TPO mimetic peptides may serve as a useful lead compound for developing a therapeutically effective thrombopoietic agent." *