TP-508

TP-508 (TP508, rusalatide) is a synthetic 23-amino-acid peptide matching amino acids 508 through 530 of human prothrombin, the precursor of thrombin (Norfleet et al., 2000). It represents part of thrombin's receptor-binding domain (Oyamada et al., 2010) but lacks the catalytic site, keeping the RGD (Arg-Gly-Asp) sequence (Tsopanoglou et al., 2004).

As Chrysalin and rusalatide acetate, the thrombin peptide TP508 reached human trials in diabetic foot ulcers and distal radius fractures; a distal radius fracture study that a 2008 review describes as phase III missed its primary clinical endpoint (Carney and Olszewska-Pazdrak, 2008).

PubChem's separate TP508 record, CID 155817508, is drawn as the C-terminal acid (C₉₇H₁₄₆N₂₈O₃₆S, 2312.4 g/mol), unlike the amide INN and acetate records.

Published work on TP-508 falls into six areas, each summarized below with its model. Most evidence is animal and cell data, and many papers list authors from the University of Texas Medical Branch group that characterized the peptide or from companies working on it.

Origin and receptor biology

In human fibroblasts, TP508 induced transcripts, including annexin V, that the PAR1-activating peptide SFLLRNP did not, pointing to a route separate from PAR1, the protease-activated thrombin receptor (Sower et al., 1999). In endothelial cells, surface-bound TP508 supported αvβ3 integrin-dependent attachment and migration, a variant with RAD in place of RGD was inactive, and soluble TP508 opposed several thrombin effects (Tsopanoglou et al., 2004). A study from Capstone Therapeutics reported RGD-dependent αvβ3 binding and nitric oxide production that an αvβ3-blocking antibody inhibited (Derkach et al., 2010). Models: human fibroblasts, endothelial cells and αvβ3-expressing kidney cells.

Skin wound closure in rats

In normal rats with full-thickness excisional wounds, one topical application of 0.1 µg TP508 left wounds on average 39% more closed than controls by day 7, with a faster early closure rate, more inflammatory cells within 24 hours and larger functional vessels in granulation tissue (Stiernberg et al., 2000).

In rat skin made ischemic with flaps or free grafts, the same application raised closure rates over the first 7 days by 30% in normal skin and bipedicle flaps, 50% in cranially based flaps and 225% in free grafts (Norfleet et al., 2000). Model: rats; both from the University of Texas Medical Branch group.

Bone repair in rats and rabbits

In a closed rat femoral fracture model, TP508 accelerated repair on destructive torsion testing, with more callus blood vessels on blinded histology and induction of early growth factor, inflammatory and angiogenesis-related genes (Wang et al., 2005). In rabbits, TP508 in PLGA microspheres raised the torsional strength of radial defects at 6 weeks and of critically sized ulnar defects at 9 weeks versus control microspheres in the opposite limb (Sheller et al., 2004).

Both papers list OrthoLogic Corp authors. An Istanbul University group gave 48 rats a single local injection of saline, 10 µg or 100 µg TP508 at the end of tibial distraction and found larger areas of new bone than with saline (Cakarer et al., 2010). Models: rats and rabbits.

Endothelial function and cardiac ischemia in pigs

In pigs with chronic myocardial ischemia, TP508 raised perfusion of ischemic regions up to 16-fold, doubled wall thickening relative to placebo and reversed impaired nitric oxide-mediated vasodilation; in human endothelial cells it raised nitric oxide output by 85% (Fossum et al., 2008).

In 14 Yucatan pigs with 60 minutes of coronary occlusion and 120 minutes of reperfusion, TP508 (a bolus, then an intravenous infusion) reduced infarct size and TUNEL staining, with no significant difference in global or regional left ventricular function (Osipov et al., 2009). In hypercholesterolemic pigs, the monomer and a dimer form both reduced infarct size versus vehicle (Oyamada et al., 2010). Models: pigs and human endothelial cells.

Radiation injury in mice

In male CD-1 mice given TP508 once, 24 hours after a lethal 9 Gy exposure, the peptide was reported to increase survival and delay mortality, with less crypt disintegration, more crypt cell proliferation and higher expression of the stem cell markers DCLK1 and LGR5 (Kantara et al., 2015). Because the TP508 peptide has a short plasma half-life, the group then tested PEGylated versions; PEG30k-TP508 extended half-life in mice about 19-fold with enhanced activity, and the paper describes TP508 as being developed as a potential nuclear countermeasure (McVicar et al., 2017). Model: mice.

Human trials as research history

A 60-subject randomized, double-blind, placebo-controlled phase I/II trial applied saline or one of two TP508 amounts (as Chrysalin) to diabetic foot ulcers. In the per-protocol population, TP508 more than doubled the incidence of complete ulcer closure, raised the mean closure rate about 80% and cut median time to 100% closure about 40%; adverse events were equal between groups (Fife et al., 2007).

A 2008 review that calls rusalatide acetate an investigational drug reports that, in a phase III distal radius fracture study, it significantly accelerated radiographic union but failed its primary clinical endpoint, time to removal of immobilization, across all randomized participants; a subset analysis in osteopenic women met it (Carney and Olszewska-Pazdrak, 2008).

A 2020 systematic review of 26 randomized growth factor and protein trials in diabetic foot ulcers found evidence lacking for all but epidermal growth factor and noted Chrysalin's 2014 discontinuation in dermatology (Mahdipour and Sahebkar, 2020). Models: people with diabetic foot ulcers or distal radius fractures.