Trigen Gmbh

Thrombosis Research Institute

Michael Finbarr Scully

Vijay Vir Kakkar

John Joseph Deadman

Goran Karl Claeson

Naoyashi Chino

Leifeng Cheng

Said Mohamed Elgendy

Xinjie Lu

Kalwant S Authi

Said Mohamed Anwar Elgendy

Dendroaspin, a polypeptide neurotoxin analogue is modified by recombinant DNA techniques, particularly &ldquo;loop grafting&rdquo; to provide a modified polypeptide. The modified polypeptide is constructed so as to retain dendroaspin activity, for example, platelet adhesion to fibrinogen, in addition to possessing one or more further biological or biochemical activities not native to dendroaspin, for example, platelet derived growth factor (PDGF) activity or hirudin activity.

Bi-or multifunctional molecules based on a dendroaspin scaffold

Peptides which act as inhibitors or substrates of thrombin are provided. The peptides of the invention have the general structural formula:

Inhibitors and substrates of thrombin

This invention provides peptides of the formula ##STR1## wherein X is H, CH.sub.3 or an N-protecting group;

Peptides which act as inhibitors or substrates of thrombin are derived from the formula: D-Phe-Pro-Arg or its analogues, wherein Phe is substituted by (a), wherein Ar.sub.1 or Ar.sub.2 are the same or different and are selected from the group consisting of phenyl, thienyl, pyridyl, naphthyl, thionaphtyl, indolyl and saturated groups corresponding to these, optionally substituted by up to three groups selected from C.sub.1 -C.sub.3 alkyl and C.sub.1 -C.sub.3 alkoxy, L.sub.1 and L.sub.2 are the same of different and are selected from the group consisting of CH.sub.2, C.sub.2 --C.sub.2, O-CH.sub.2, S-CH.sub.2, Ar-L taken together optionally means H, diphenyl-methyl, fluorenyl or saturated groups corresponding to these, but one of the Ar-L cannot be H when the other [CH.sub.2 ].sub.n -Q, (c) where Q=H, amino, amidino, imidazole, guanidino or isothioureido and n=1-5, preferably 3-5, or C.sub.3 -C.sub.9 alkyl and C.sub.5 -C.sub.10 aryl or alkylaryl optionally substituted by up to three groups selected from hydroxy and C.sub.1 -C.sub.4 alkoxy; Z=CN, COR.sub.1, (d) or (e), where R.sub.1 =H, OH, CH.sub.2 Cl, CH.sub.2 --C.sub.2 --CO--pip, CF.sub.2 --CF.sub.2 --CO--pip, (f), (g), CH.sub.2 --C.sub.2 --CO--Pro--NHEt, CF.sub.2 --CF.sub.2 --CO--Pro--NHEt or a chromophoric group e.g. pHA, MCA, R.sub.2 and R.sub.3 are the same or different and are selected from the group consisting of OH, OR.sub.6 and NR.sub.6 R.sub.7, or R.sub.2 and R.sub.3 taken together represent the residue of a diol; where R.sub.6 and R.sub.7, which are the same or different, are C.sub.1 -C.sub.10 alkyl, phenyl or C.sub.6 -C.sub.10 arylalkyl, R.sub.4 and R.sub.5 are the same or different and are selected from R.sub.2, R.sub.3, Gly-pip, Ala-pip or Gly-Pro-NHEt.

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Crays Hill, United Kingdom

Michael Finbarr Scully