Protease inhibitors polymers

Foscarnet (Foscavir) [Antiviral] Uses CMV retinitis acyclovir-resistant hCTpes Infxns Action -1- Viral DNA polym ase RT Dose CMV retinitis Induction 60 mg/kg IV qSh or 100 mg/kg ql2h X 14—21 d Meant 90-120 mg/kg/dIV (Moo.-Fiti ) Acyclovir-resistant HSV Induction 40 mg/kg IV q8-12h x 14—21 d use central line -1- w/ renal impair Caution [C, —] T Sz potential w/ fluoroquinolones avoid n hrotoxic Rx (cyclosporine, aminoglycosides, ampho B, protease inhibitors) Contra CrCl <0.4 mL/min/kg Disp Inj SE Nephrotox, electrolyte abnormalities Interactions T Risks of Sz W/ quinolones t risks of n hrotox W/ aminoglycosides, amphotCTicin B, didanosine, pentamidine, vancomycin EMS Known to cause electrolyte disturbances (extremity numbness paresthesia indicates electrol5rte unbalance) monitor ECG OD May cause extremity numbing, and Szs hydrate w/ IV fluids... 

Polymers may also inhibit proteolytic enzymes or be used to augment the activity of proteolytic inhibitors (Table 11.6). The administration of small molecule protease inhibitors in conjunction with the peptide, however, has been examined with some success (Fujii et al. 1985) however, the ability of these molecules to protect the protein has been hampered by the fact that they tend to cause systemic side effects (Yagi et al. 1980 McCaffrey and Jamieson 1993 Plumpton et al. 1994). Many protease inhibitors have been specific for the proteases in the stomach and intestine, but some of these factors are not specific and some control over absorption of the... 

Polymers that are protease inhibitors and polymer-inhibitor conjugates are now widely investigated for their ability to protect proteins and peptides from proteolytic degradation. These molecules are effective in the immediate area surrounding the delivery device, so the effects on proteins that have diffused far from the delivery device are limited. Due to the fact that bioadhesives were used as the conjugating polymer, the delivery device may adhere to the intestinal lining. If this does happen, the diffusional distance of the protein from the device to the intestinal wall will be quite short. One barrier that the protease inhibitors do not affect is the cellular barrier. Biomacromolecules must still find a method to enter the cells or be taken up by phagocytosis. 

Inhibitors of proteases have also been developed from polymers. These molecules are as simple as a polymer chain, or much more complex. The mechanisms for protease inhibition are variable depending upon the type of molecule used specific protease inhibitors are available for conjugation to a polymer while other polymeric inhibitors inhibit all divalent cation dependent proteases. The development of these inhibitory polymers and polymer conjugates greatly increase the possibility to protect proteins from degradation in the gastrointestinal tract. 

Furthermore, the sulfonamide bond is expected to possess enhanced metabolic stability with structural similarities to the tetrahedral transition state involved in amide bond enzymatic hydrolysis, thus making sulfonamide peptides interesting candidates in the development of protease inhibitors and new drugs. The oligomers and polymers should also be interesting molecular scaffolds, with specific secondary structures enforced by hydrogen bonding)100,101 ... 

Novel Polymer and Linker Reagents for the Preparation of Protease-inhibitor Libraries... 

In this article we will focus on two types of novel polymer reagent useful for preparation of protease inhibitor libraries. Oxidizing polymers have been developed for synthesis of amino and peptide aldehydes (Chapter 3) which are an important class of protease inhibitors by themselves and can also be used as reactive electrophiles in subsequent transformations. 

To gain access to a broader spectrum of natural products including protease inhibitors, C-C-bond formation is often required in central steps. For this purpose polymer-supported carbanion equivalents have been investigated (Chapter 4). Several strategies leading to supported acyl anion equivalents are presented these have been employed for general synthesis of protease inhibitors containing the a-hydroxy-jS-amino motif. 

Protease-inhibitor Synthesis - A Demanding Test Case for Polymer Reagents... 

Oxidizing polymers and polymer-supported carbanion equivalents, in particular, have been employed successfully for preparation of protease inhibitor collections as a practically relevant example. With peptide aldehydes and differently substituted a-hydroxy-jS-amino carbonyl moieties two inhibitory motifs have been prepared with hitherto unprecedented ease and efficiency. Now it remains to be demonstrated that the synthetic methodology as introduced here is capable of assisting the identification of novel biologically active structures. 

High-throughput synthesis and combinatorial chemistry employing polymer supports, with computer-based rational design, are important tools for systematic optimization of the affinity, selectivity, and bio-availability of protease inhibitors. It is very likely that currently available isosteres will not suffice for addressing the natural selectivity of proteases. Thus, synthetic methodology must be devised not only to decorate a predefined isosteric core but to define novel active site binders. 

Protease Inhibitors Based on Multifunctional Mucoadhesive Polymers. . 75... 

Yamamoto et al. [4] showed that 0.01% aprotinin (a serine protease inhibitor) reduced the metabolism of insulin and proinsuHn in homogenates of albino rabbit buccal mucosa, which otherwise would have occurred at 70-80% within 2.5 hours. Moreover, Lehr et al. suggest that polycar-bophil, a bioadhesive polymer, may protect some peptides from proteolysis, though the mechanism of this is unknown [5]. Others [6] have developed a series of pro-dmgs for peptides, with the aim of overcoming the metabohc barrier imposed by different peptidases. Stable prodrugs proved to be N-hydroxymethylated derivatives of the assessed dipeptides Gly-L-Leu and Gly-L-Ala [6]. 

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