Peptides that bind to fibrin but not to fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar=aromatic, Tn6), X2CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to fibrin at ~2 sites with Kd=4.1 μM, 4.0 μM, and 8.7 μM, respectively, whereas binding to fibrinogen was at least 100 – fold weaker. The peptides also bind to the fibrin degradation product DD(E) with similar affinity to that measured for fibrin. The Tn7 and Tn10 peptides bind to the same site on fibrin while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential imaging applications and these retained fibrin binding affinity and specificity in plasma. Relaxivity and binding studies on the GdDTPA derivatives revealed that an N-terminal glycyl linker had modest effect on fibrin affinity but resulted in lower fibrin-bound relaxivity.
Magnetic resonance imaging (MRI) contrast agents are utilized adjunctively to enhance the contrast between normal and abnormal structures on MRI scans. Along with the rapid evolution of the field has come a new appreciation for the medicinal chemistry of this unique class of metallopharmaceuticals. The efficacy of MRI agents is a complex function of chemical, biophysical, and pharmacological properties, which must be married in a package of exquisite safety. This report illustrates the wide range of medicinal chemistry relevant to existing agents that are either approved or in clinical development, as well as concepts, which may result in exciting new pharmaceuticals in the future.
Probing in contrast: Four gadolinium‐DTPA moieties (DTPA=diethylenetriaminepentaacetic acid) and two fibrin‐specific cyclic peptides are linked by a compact triethylenetetraamine core (see scheme) to create a highly sensitive probe for molecular MR imaging of thrombosis. The contrast agent has a high molecular relaxivity, and the dual peptide construct provides five‐fold higher fibrin affinity than the monovalent analogue. This bivalent probe showed significant specific thrombus uptake in an in vivo model of thrombosis.
A strategy for preparing high relaxivity, metabolically stable peptide-based MR contrast agents is described.The chemical and topological diversity of peptides offer tremendous possibilities to identify new diagnostic imaging compounds. Peptides have been widely used to target an imaging probe to a specific protein or receptor and thereby provide greater specificity. Typically an imaging reporting moiety (e.g. positron emitter, gamma emitter, paramagnetic ion, near infrared fluorophore) is conjugated to the peptide. The site of conjugation, the linker, and the type of imaging reporter all play a role in determining biological activity and pharmacokinetics. 1, 2 For peptide-based magnetic resonance imaging (MRI) contrast agents, an additional factor is detection sensitivity of the imaging probe. 3 Multiple copies of the MR active reporter, typically a gadolinium complex, are required to provide robust image contrast.An additional major challenge to creating new drugs from peptides is peptide degradation by endogenous peptidases. There are numerous medicinal chemistry approaches to improve peptide stability, biological activity, and/or bioavailability that increase in complexity from modified peptides to pseudopeptides to small molecule peptidomimetics. 4,5 In this report, we explore the potential of using the imaging reporter to block peptidase activity.We, 6-9 and others, 10-14 have been interested in developing gadolinium-based peptide-targeted MR imaging agents. Compared to other modalities, MRI provides a favorable combination of high spatial resolution, depth penetration, and lack of ionizing radiation. Unlike nanoparticles, these relatively small molecules can rapidly reach targets in extravascular spaces and can be readily excreted through the kidneys to reduce/avoid long-term gadolinium retention and toxicity. On the other hand, extravasation into the kidneys and liver exposes these compounds to a range of peptidases.There is some flexibility as to where and how the gadolinium chelates are conjugated to the peptide. Conjugation is possible at the N-or C-terminus and/or within the peptide structure. 6 We recently reported some fibrin-specific peptides conjugated with one or four [Gd (DTPA)] 2− moieties. 8 The construct with highest affinity had two peptides linked via their Nterminus to a GdDTPA tetramer, i.e. Pep N -Gd 4 -N Pep, termed EP-1084 (Cmpd 1 in Scheme
Bacterial infections can have adverse effects on the efficacy, lifetime and safety of an implanted device and are the second most commonly attributed cause of orthopedic implant failure. We have previously shown the assembly of PEGylated titanium-binding peptides (TBPs) on Ti to obtain a bacteriophobic surface coating that can effectively resist protein adsorption and Staphylococcus aureus (S. aureus) adhesion. In the present study, we examine the effect of multiple TBP repeats on coating performance in vitro. Mono, di, and tetravalent peptides were synthesized and assessed for binding affinity and serum stability. PEGylated analogs were prepared and evaluated for their effect on S. aureus attachment and biofilm formation. Coating performance improved with the number of TBP repeats, with the tetravalent coating, TBP4–PEG, showing the best performance in all assays. In particular, TBP4–PEG forms a serum-resistant surface coating capable of preventing S. aureus colonization and subsequent biofilm formation. These results further support the role that multivalency can play in the development of improved surface coatings with enhanced stabilities and efficacy for in vivo clinical use.
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