Intramers for Protein Function Analysis and Drug Discovery

One of the biggest challenges in today's life sciences is to gain a detailed understanding of the function and interplay of the numerous proteins in different organisms, tissues, cell types, and conglomerate protein complexes. One of the most efficient ways of studying protein function in the context of the living cell or organism is the application of a small molecule drug that exhibits high specificity, affinity, and inhibitory activity to the protein under investigation. However, such...

Age Related Macular Degeneration

AMD is a chronic and progressive disease of the eye that primarily affects older and Caucasian populations. AMD is in fact the leading cause of blindness in people above 50 years of age in the developed world (Resnikoff et al., 2004). AMD affects the central portion of the retina, which is called the macula. The macula is important for central vision. Patients who lose central vision have dif- ficulty with activities of daily living, such as reading, driving, meal preparation, and housework...

Vascular Endothelial Growth Factor VEGF

Angiogenesis plays a critical role in numerous physiological and pathological states. Vascular endothelial growth factor (VEGF) is the best characterized factor involved in benign and neoplastic angiogenesis and represents a promising target in anticancer and other anti-angiogenic therapies (Rosen, 2001, 2002). Elevated VEGF levels are associated with ocular neovascularizations including diabetic retinopathy (Adamis et al., 1994), retinopathy of prematurity (Pierce et al., 1995), and macular...

Bioactive Spiegelmers

Williams et al. showed in 1997 that selection-reflection is a viable means of producing bioactive and nuclease-resistant ligands for bioactive target molecules (Williams et al., 1997). Selecting for the all-d form of vasopressin - a cyclic non-apeptide - they finally generated a 55-nucleotide l-DNA that binds to the natural vasopressin with equal (low micromolar) affinity. This DNA Spiegelmer was active in an assay using cultured renal cells which expressed the V2 receptor, antagonizing...

F

FDA see Food and Drug Administration fitness landscape 54, 57-58, 60-62, 64, 85 fitness value 57 flow cytometry 324 fluorescence signaling 246, 319 fluorescence intensity (FI) 314 fluorescence lifetime (FLT) 314 fluorescence polarization (FP) 314, 316 fluorescence resonance energy transfer (FRET) 303-304, 319 Food and Drug Administration (FDA) 363, 383-384, 405, 443, 446, 452 formulations 383 - polyalginate polylysine microparticles 386 FRET see fluorescence resonance energy transfer (FRET)...

Future Prospects for Aptamer Therapeutics

High-affinity aptamers can be generated readily against a variety of therapeutic protein targets, best illustrated perhaps, by the steady progression of aptamers selected against extracellular growth factors (VEGF, PDGF) and components of coagulation (thrombin, Factor IXa) and complement (C5) pathways through preclini-cal and clinical testing. With remarkable target specificity, versatile pharmaco-kinetic properties, ease of synthesis, and relatively low manufacturing costs, apta-mers are...

Conversion of Aptamers into Small Molecule Lead Compounds

Many pharmaceutical companies are primarily concerned with developing orally administered small-molecule drugs. This is because small-molecule drugs are inexpensive to produce and can potentially become blockbusters. Initially, compound libraries are screened in cell-based or biochemical assays to identify hits these are subsequently optimized in pharmaceutical hit-to-lead programs. Classical screening approaches are often supported by in silico methods to aid drug development. The ultimate...

Rationale for Targeting VEGF

Angiogenesis Foundation

Angiogenesis - the growth of new blood vessels - is a central component of many human disease processes (Witmer et al., 2003). There are several examples that have been areas of very active research. As solid tumors grow they require an ever-increasing supply of oxygen and nutrients, and hence develop their own vascular beds in order to meet this requirement. In patients with diabetes mellitus, chronically elevated blood glucose levels result in damage to small blood vessels and resultant...

Aptamers to Natural Products

Caffeine Aptamer Interaction With Target

Jenison et al. (1994) selected an RNA aptamer that binds to the alkaloid theophyl-line with high sensitivity and high specificity. Theophylline is used as bronchodi-lator in the treatment of asthma, bronchitis, and emphysema, but because of its narrow therapeutic index, serum levels must be monitored carefully to avoid serious poisoning. Theophylline is also chemically similar to theobromine and caffeine (Fig. 4.5), which may be present in serum samples due to consumption of coffee or...

Neuropeptide Calcitonin Generelated Peptide

Cerebral vessel vasodilation is a widely accepted hypothesis for the cause of migraine headaches. Neuro calcitonin gene-related peptide 1 (a-CGRP) induces vasodilation, and inhibition of this target may play a role in treating such headaches (Renfrey et al., 2003). Using a tailored-SELEX approach with an RNA-based library, 15 rounds of selection against rat a-CGRP were performed and a spiegelmer named STAR-F12 bound to a-CGRP with a Kd of 2.5 nmol L and inhibited a-CGRP-induced cAMP with an...