By K. Curtis. Grambling State University. 2018.

Endocytosis is defined as the internalization of plasma membrane with concomitant engulfment of extracellular material and extracellular fluid order 60 caps pilex overnight delivery androgen hormone therapy. Pinocytosis is a non-specific process that goes on continually in all cell types pilex 60caps otc prostate 75 psa, in which the plasma membrane invaginates and forms an inward channel, into which extracellular fluid flows (Figure 1. Solutes dissolved in the extracellular fluid, including large (soluble) macromolecules, may flow with the extracellular fluid into the invaginations and become internalized. Alternatively, uptake may involve: • adsorptive pinocytosis, in which macromolecules bind to non-specific membrane receptors, prior to pinocytosis; • receptor-mediated pinocytosis, in which macromolecules bind to specific membrane receptors, prior to pinocytosis. The pinocytic vesicles (endosomes) migrate inwardly and fuse with lysosomes, which contain many lyosomal enzymes, to form secondary lyosomes. The ligand is degraded by the lysosomal enzymes, the degraded products are released and the membrane is recycled back to the plasma membrane. Alternatively, the secondary lysosomes can fuse with the cell membrane, leading to exocytosis of their contents, and the membranes are recycled back to the plasma membrane. Thus pinocytosis offers a pathway through which large macromolecules, which are otherwise incapable of passing through the membrane, may be taken up by cells. In some cases, following uptake of a drug via receptor-mediated pinocytosis, the endosomes carrying the drug actually bypass the lysosomes and migrate toward the basolateral membrane, resulting in the release of the undegraded drug into the extracellular space bounded by the basolateral membrane. This process, known as transcytosis, represents a potentially useful and important pathway for the absorption of high molecular weight drugs such as peptides and proteins. Indeed, some peptides and proteins are known to enter intestinal mucosal cells through pinocytosis; furthermore, a few peptides and proteins (including immunoglobulin G, nerve growth factor and epidermal growth factor) have been reported to reach blood vessels in the lamina propria and the portal venous circulation. This process may be facilitated by serum proteins knows as opsonins, which cover the particulate and promote adsorption and ingestion. The extent and pattern of opsonization depends highly on antigen surface characteristics such as charge and hydrophilicity. When digestion is complete, the lysosomal membrane may rupture, discharging its contents into the cytoplasm. Fixed macrophages are found lining certain blood and lymph-filled spaces, such as the sinusoids of the liver (these cells are commonly referred to as Kuppfer cells), bone marrow and spleen. For the purpose of completeness, the process of phagocytosis has been described briefly here. The process of phagocytosis is of particular relevance when particulate delivery systems, such as microspheres, liposomes and other advanced delivery systems (described in Chapter 5), are used. Phagocytic processes are also finding applications in oral drug delivery and targeting. Specialized epithelial cells known as M cells, which overly lymphoid sections of the gastrointestinal tract, may be involved in the phagocytic uptake of macromolecules and microparticles from the gut (see Section 6. Pore transport A further mechanism of transcellular transport is via the aqueous pores which exist in many lipid membranes. However, most drugs are generally much larger (≥1 nm in diameter) than the pore size, and this route is therefore of minor importance for drug delivery. These properties will influence the route and mechanism of drug absorption through the mucosa. For example, it is not unreasonable to assume that: • low molecular weight hydrophilic compounds would tend to be absorbed via the paracellular route, moving between the epithelial cells; • lipid-soluble drugs would usually absorbed via transcellular passive diffusion, diffusing through the lipidic membrane barrier; • macromolecules may be absorbed via endocytic processes; • drugs bearing structural similarities to endogenous nutrients may be absorbed via carrier-mediated mechanisms. However, this is a rather simplistic view and it is important to realize that these considerations are only broad generalizations. Thus although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via other routes and mechanisms. In particular, drugs that are absorbed via active mechanisms are often also absorbed, to a (much) lesser extent, via passive diffusion mechanisms. A brief description of the effect of the physicochemical properties of the drug on the absorption process is given below and is discussed in more detail in the relevant chapters. A measure of the lipid solubility of a drug is given by its oil/water equilibrium partition coefficient.

Peptides are particu- larly amenable to modifcations to confer improved selectivity quality 60 caps pilex androgen hormone of pregnancy, potency order pilex 60caps with visa prostate cancer emedicine, and stability [51], while maintaining bioactivity [69]. The aim of this chapter is to illustrate that peptides isolated from natural sources have exciting potential as drugs. Examples from various bacterial, plant and ani- mal sources will be described to highlight the large diversity of chemical structures, modes of action and biological applications of peptide. Strategies to overcome possi- ble drawbacks associated with the application of peptides as drugs will be discussed. They act as endogenous antibi- otics, inducing the direct destruction of microorganisms. The cationic group is the largest and is discussed in more detail in this chapter, as the anionic group is considered to have lower activity [81]. To highlight the diversity of these peptides, we have chosen examples based not only on their thera- peutic value, but also on the novelty of their structures and modes of action. The group includes peptides having linear (noncross-linked) structures and forming α-helical structures as well as Cys-rich peptides with disulfde bonds and β-sheet structures [23]. The α-helical peptides are particularly abundant in the extracellular fuids of insects and amphibians and frequently exist as unstructured monomers in solution, becoming helical upon interaction with phospholipid membranes [84–86]. The β-sheet peptides have a diverse range of primary structures and often possess Cys residues in disulfde bonds, as is demonstrated for example by the defensin family [87]. Conventional antibiotics are largely ineffective against cystic fbrosis due to elevated salt concentrations that inhibit the usual antibacterial defenses in the lung [89]. However, the use of amphibian skin as a source of antibiotics is not restricted to this example, and several other peptide families with antimicrobial activity have been identifed, including temporins [94], bombinins [95], and bombinins H [96]. Because of their small size and potent activities, they are of particular interest for drug design. The bombinin family comprises 20–27 residues peptides with activ- ity against both Gram-negative bacteria and Gram-positive bacteria [95, 97]. These peptides generally adopt a random coil structure an aqueous environments whereas in an apolar environment they have an amphipathic α-helix structure [97]. Although these peptides are antimicrobial, they show no cytolytic activity against mammalian cells [95, 97]. Peptides belonging to this family contain 17–20 residues, and d-amino acids are found in some peptides in this class, increasing their stability [96]. Like bombinins, these peptides typically adopt a random coil structure in an aqueous environment and an amphipathic α-helix in apolar environments [98, 99]. The presence of d-amino acids results from a post-translational modifcation involving a l–d isomerization [100], with these peptides displaying better antimicrobial activity against some bac- terial strains than the pure l-isomer [98]. These peptides have potent activity against Leishmania by rapid perturbation of the plasma membrane, and are of interest for the development of new drugs against this global infectious disease [102]. Temporins were frst identifed in the frog Rana temporaria [94] and are the shortest α-helical peptides isolated from amphibians (10–14 residues). They tend to form an amphipathic α-helical structure in hydrophobic environments, and have a net charge of 0 to +3 [103]. They are active against a wide range of pathogens (bacteria, viruses, fungi, yeasts, and protozoa) [94, 104–106] and are not toxic to mammalian cells at concentrations that kill microbes [94]. An exception is temporin L, which is highly active on bacteria, erythrocytes, and cancer cells [107]. Peptides belonging to temporin family have attractive properties, such as high activity in physiological conditions, high stability in serum [106], and low cost synthesis due to their short amino acid sequence [108], making them exciting peptides for drug design applications. Defensins are cysteine-rich peptides that participate in the host defense of mam- mals [109], insects [110], and plants [111]. They are characterized by intramolecular disulfde bonds that stabilize the structures, and frequently contain small β-sheet structures [87]. Although defensins have been isolated from many species, the α- and β-defensins of human origin are the best studied. In the α-defensins, the cysteines are paired with a 1–6, 2–4, and 3–5 confguration, whereas in the β-defensins the pairing is 1–5, 2–4, and 3–6 [72]. Many potential therapeutic applications have been suggested for defensins due to their activity against Gram-positive and Gram-negative bacteria, fungi, viruses, and cancer cells [109]. Fundamental differences exist between microbial and mammalian cells, including membrane com- position and architecture, transmembrane potential and polarization, and structural features, including the presence of a cell wall [83].

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This concept is different from zero-order elimination 60 caps pilex for sale androgen hormone oestrogen, in which the amount of drug eliminated for each time interval is constant order pilex 60caps with visa prostate cancer urologist vs oncologist, regardless of the amount of drug in the body. With the first-order elimination process, although the amount of drug eliminated may change with the amount of drug in the body, the fraction of a drug in the body eliminated over a given time remains constant. In practical terms, the fraction or percentage of drug being removed is the same with either high or low drug concentrations. For example, if 1000 mg of a drug is administered and the drug follows first-order elimination, we might observe the patterns in Table 2-4. The actual amount of drug eliminated is different for each fixed time period, depending on the initial amount in the body, but the fraction removed is the same, so this elimination is first order. Because the elimination of this drug (like most drugs) occurs by a first-order process, the amount of drug eliminated decreases as the concentration in plasma decreases. On the other hand, with zero-order elimination, the amount of drug eliminated does not change with the amount or concentration of drug in the body, but the fraction removed varies (Figure 2-7). For example, if 1000 mg of a drug is administered and the drug follows zero-order elimination, we might observe the patterns in Table 2-5. If the plasma drug concentration is continuously measured and plotted against time after administration of an intravenous dose of a drug with first- order elimination, the plasma concentration curve shown in Figure 2-8 would result. To predict concentrations at times when we did not collect samples, we must linearize the plot by using semilog paper (Figure 2-9). For a drug with first-order elimination, the natural log of plasma concentration versus time plot is a straight line. Note that for a drug with zero-order elimination, the plot of the plasma concentration versus time is linear (plot A in Figure 2-10), whereas on semilog paper (representing the natural log of plasma concentration versus time) it is a curve (bottom plot in Figure 2-10). If the natural log of a plasma drug concentration versus time plot is linear, it generally can be assumed that the drug follows first- order elimination. The pharmacokinetic parameters for these drugs are not affected by the size of the dose given. As the dose and drug concentrations increase, the amount of drug eliminated per hour increases while the fraction of drug removed remains the same. As the dose and drug concentration increase, the amount of drug eliminated per hour does not increase, and the fraction of drug removed declines. The size of the arrow represents the amount of drug eliminated over a unit of time. Plasma drug concentration versus time after an intravenous (bolus) drug dose, assuming a one-compartment model with first-order elimination (linear y-scale). Plasma drug concentrations versus time after an intravenous (bolus) drug dose, assuming a one-compartment model with zero-order elimination (A, linear plot; B, log plot). A dose of 1000 mg of a drug is administered to a patient, and the following concentrations result at the indicated times below. Plasma Concentration Time after Dose (mg/L) (hours) 100 2 67 4 45 6 An estimate of the volume of distribution would be: A. If a drug is extensively distributed to tissues, its apparent volume of distribution is probably very: A. For the body fluid compartments below, rank them from the lowest volume to the highest, in a typical 70-kg person. Plasma refers only to the fluid portion of blood, including soluble proteins but not formed elements. Total body clearance is the sum of clearance by the kidneys, liver, and other routes of elimination. To determine drug clearance, we must first determine whether a drug best fits a one- or two- compartment model. With a drug that follows first-order elimination, the amount of drug eliminated per unit time: A. You can determine the correct answer from the units in the numerator and denominator. The volume is therefore determined from the dose, or amount of drug given, and the resulting initial concentration. To find the initial concentration, plot the given plasma concentration and time values on semilog paper, connect the points, and read the value of the y-axis (concentration) when x (time) = 0. You can then determine the volume of distribution using the equation volume of distribution = dose/initial concentration.

Crutchfield (32) also reports significant relationships between responsiveness and such variables as impulsiveness generic 60caps pilex free shipping prostate 85, dominance discount pilex 60 caps without a prescription prostate 75, flexibility, spontaneity, femininity, and independence of judgmemt, as well as differences between groups in self-perception based on results from adjective check lists. In a study utilizing "normal" subjects, Cervin (27) selected as subjects high and low scorers on several pencil and paper tests of emotional stability. Highly unstable subjects were found to be significantly more likely to change their opinions under opposition. Levine, Laffal, Berkowitz, Lindemann, and Drevdahl (84) contrasted the variability in individual scores on the autokinetic task for patients in a Veterans Administration hospital. The psychiatric group was found to be more variable in perceptual judgments and to show less convergence toward group norms than the "control" group. Didato (36) obtained similar results for schizophrenic compared with normal subjects. Degree of regression in chronic schizophrenia has been reported by Spohn (125) to be related to the tendency to modify judgments in accordance with group norms, with those patients rated as moderately regressed showing more conformity in perceptual judgments than those rated as markedly regressed. Blake, Helson, and Mouton (18) investigated the generality issue for responses to various tasks under simulated group conditions. Generality of susceptibility was demonstrated by individual consistency for all tasks. Helson, Blake, Mouton, and Olmstead (63) demonstrated that individuals shifting their judgments on a larger number of attitude items moved closer to the contradictory opinions of others than those who shifted less frequently. Crutchfield (34) found the split-half reliability of individual conformity scores for a twenty-one item test to be +. Luchins (90) has reported a significant rank order correlation between degree of agreement with responses given by an assistant both in the preliminary and in the experimental series (see preceding). Both subjects who conformed and those who resisted initially tended to maintain their behavior throughout a series of trials. Results suggest that those who are more susceptible to conformity pressures are more likely to be submissive, low in selfconfidence, less intelligent, less original, show less nervous tension, score higher on authoritarian scales, score on the simplicity end of the dimension of the complexity-simplicity scale, show greater dependence on the perceptual field, and comply with requests more frequently. Several investigations reveal that conformity tendencies are geiteral across several tasks. Combinations of Variables Significant interactions between factors were found in some studies, and pooling effects were obtained by simultaneous variations in others. Variations in Stimulus and Background Dimensions A strong request complied with by another person has been found by Blake, Mouton, and Hain (19) to produce the highest frequency for signing a petition (see above). Highest frequency of volunteering has been obtained by Rosenbaum (112) (see above). Freed, Chandler, Mouton, and Blake (45) found that the largest and smallest number of violations respectively occurred when subjects saw an assistant (a) violate a "weak" sign forbidding entry and (b) conform to a strong" sign (see preceding). Blake, Helson, and Mouton (18) have varied difficulty of arithmetic items in combination with degree of discrepancy between correct answers and erroneous reports by background subjects. They report greatest shifting for more difficult items when the erroneous reports were only slightly divergent from the correct answers and the converse (see above). Uncertainty of judgment (or difficulty) also has been varied by Deutsch and Gerard (35). Subjects were found to be most susceptible when responses were given from memory, and when group members were told that the group would be rewarded for accuracy with a prize. Differences between manners of presentation were not found when subjects wrote their responses prior to hearing the reports of others (see above). Weiner (132) reported positive relationships among stimulus ambiguity, degree of certainty of judgment, discrepancy from the norm, and conformity (see above). Variations in Stimulus Dimensions and Sex Coleman, Blake, and Mouton (31) have demonstrated a significant relationship between task difficulty, susceptibility, and sex of subject. Men and women college students responded to information items after hearing the reports of two other men or women in the simulated group situation. Conformity was found to be positively and significantly related to difficulty of item for both men and women. Variations in Background Dimensions Schachter, Ellertson, McBride, and Gregory (116) found that pressures from other group members to increase production were equally effective for both high and low cohesion groups, and influences to decrease production successful only for the high cohesion groups (see above). Gerard (47) found that the higher the attractiveness of the reference group and the greater the initial agreement, the smaller the amount of shifting under exposure to influences (see above). Dittes and Kelley (37) have investigated changes in public and private opinion by group members varying in feelings of acceptance.

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Mechanism of action: Blocks acetylcholine effects at muscarinic receptors throughout the body cheap 60caps pilex visa prostate cancer xgeva. Mechanism of action: Binds to opioid receptors and blocks ascending pain pathways order pilex 60 caps overnight delivery prostate yellow sperm. Warnings/precautions • Use with caution in patients with head injury with increased intracranial pressure, serious alcoholism, prostatic hypertro- phy, chronic pulmonary disease, severe liver or kidney disease, disorders of biliary tract, and in postoperative patients with pulmonary disease, suicidal or addiction-prone patients. If nausea and vomiting persist, it may be necessary to administer an antiemetic, eg, droperidol or prochlorperazine. Editorial comments • Proproxyphene increases plasma levels of the following drugs: carbamazepine, warfarin, tricyclic antidepressants. Mechanism of action: Competitive blocker of β-adrenergic receptors in heart and blood vessels. If necessary to dis- continue, taper as follows: Reduce dose and reassess after 1–2 weeks. Clinically important drug interactions • Drugs that increase effects/toxicity of β blockers: reserpine, bretylium, calcium channel blockers. If hypotension occurs despite correction of bradycardia, administer vasopressor (norephinephrine, dopa- mine, or dobutamine). Stop therapy and administer large doses of β-adrenergic bronchodilator, eg, albuterol, terbutaline, or aminophylline. Some advocate discontinuing the drug 48 hours before surgery; others recommend withdrawal for a considerably longer time. These are drugs of first choice for chronic stable angina in conjunction with nitroglycerin. Mechanism of action: Inhibits synthesis of thyroid hormones; blocks thyroid gland oxidation of iodine. Adjustment of dosage • Kidney disease: Creatinine clearance 10–50 mL/min: 75% of normal dose; creatinine clearance <10 mL/min, 50% of normal dose. Onset of Action Peak Effect Duration 24–36 h 2–10 wk — Food: May be taken with food. Warnings/precautions: Use with extreme caution in patients receiving other drugs that are potentially able to cause agranu- locytosis, kidney disease, elderly. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Clinically important drug interactions: Drugs that increase effects/toxicity of propylthiouracil: antineoplastic agents, lithium, potassium or sodium iodide, phenothiazines. Parameters to monitor • Signs and symptoms of hyperthyroidism or thyrotoxicosis: tachycardia, insomnia, diaphoresis, heat intolerance, weight loss, diarrhea. Mechanism of action: Forms a complex with heparin that neu- tralizes the anticoagulant action. Onset of Action Peak Effect Duration 30–60 s <5 min 2 h Adjustment of dosage: None Food: Not applicable. Warnings/precautions • Use with caution in patients with postcardiac surgery, allergic reaction to fish, previous sensitization to protamine (present in protamine zinc insulin). Advice to patient: Use caution in activities that may cause bleed- ing such as shaving with razor, brushing teeth, receiving injections. Such restrictions are necessary until the risk of hemorrhage is no longer present. These values should be obtained 5–15 minutes after adminis- tration of protamine and repeated in 2–8 hours. Be aware that bleeding may recur 8–9 hours after therapy due to rebound; rebound may occur even as late as 18 hours after administration of protamine. Editorial comments • Use with caution in the elderly because of possibility of severe cardiovascular side effects. Contraindications: Hypersensitivity to pyrazinamide, severe liver disease, acute gout. Warnings/precautions • Use with caution in patients with diabetes mellitus, renal failure, chronic gout. Advice to patient • To minimize possible photosensitivity reaction, apply adequate sunscreen and use proper covering when exposed to strong sunlight. Clinically important drug interactions: Pyrazinamide decreases effects/toxicity of isoniazid.

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There’s more Thiotepa is used for the treatment of intracavitary effusions (accu- mulation of fluid in a body cavity) cheap pilex 60caps otc prostate cancer level 7. It’ll take your breath away Adverse When used with succinylcholine discount 60caps pilex fast delivery mens health home workout, thiotepa may cause prolonged respirations and apnea (periods of not breathing). Thiotepa ap- reactions pears to inhibit the activity of cholinesterase, the enzyme that de- to thiotepa activates succinylcholine. Because their action resembles that of a and pancytopenia (defi- bifunctional alkylating drug, they are referred to as alkylating-like ciency of all cellular ele- drugs. Pharmacokinetics Other adverse reac- The distribution and metabolism of carboplatin aren’t defined tions include: clearly. It (commonly) has an initial half-life of 1 to 2 hours and a terminal half-life of • stomatitis and ulcera- 21⁄2to 6 hours. In patients with decreased renal function, the ter- tion of the intestinal mu- minal half-life of carboplatin may last from 30 to 300 hours. Oxali- cosa (especially at bone platin is 70% to 90% bound to plasma proteins, and the protein- marrow transplantation binding increases over time. It’s widely distributed into most body doses) tissues and is eliminated in phases. Into the lungs and peritoneum When administered intrapleurally (into the pleural space around the lung) or intraperitoneally (into the peritoneum), cisplatin may exhibit significant systemic absorption. The drug undergoes some liver metabolism, followed by ex- cretion through the kidney. Going platinum Platinum is detectable in tissue for at least 4 months after admin- istration. Pharmacotherapeutics These alkylating-like drugs are used in the treatment of several Adverse cancers. Normal cells that are reproducing actively, as well as the cancer cells, are af- fected by the antimetabolites. Folic acid analogues Although researchers have developed many folic acid analogues, the early compound methotrexate remains the most commonly used. Pharmacokinetics Methotrexate is well absorbed and distributed throughout the body. It can accumulate in any fluid collection, such as ascites or pleural or pericardial effusion, possibly resulting in prolonged elimination and higher than expected toxicity, especially myelo- suppression. Metabolism and excretion Although methotrexate is metabolized partially, it’s excreted pri- marily unchanged in urine. A disappearing act Methotrexate exhibits a three-part disappearance from plasma; the rapid distributive phase is followed by a second phase, which reflects kidney clearance. The last phase, the terminal half-life, is 3 to 10 hours for a low dose and 8 to 15 hours for a high dose. Methotrexate is especially useful in treating the most Pharmacodynamics common childhood Methotrexate reversibly inhibits the action of the enzyme dihydro- leukemia. Folinic acid is used in high-dose methotrexate therapy to help prevent cell death. Kidney concerns • Salicylates and nonsteroidal anti-inflammatory drugs, especially With high doses, kidney diclofenac, ketoprofen, indomethacin, and naproxen, also in- toxicity can also occur crease methotrexate toxicity. It consists of a sugar, a nitrogen-containing Climbing the ladder to understanding base, and a phosphate group. Cytosine and thymine are pyrimidines; After pyrimidine analogues are converted into adenine and guanine are purines. Pharmacokinetics Because pyrimidine analogues are poorly absorbed when they’re given orally, they’re usually administered by other routes. Pharmacodynamics Pyrimidine analogues kill cancer cells by interfering with the nat- ural function of pyrimidine nucleotides. Adverse reactions to pyrimidine analogues Like most antineoplastic drugs, pyrimidine ana- • Diarrhea logues can cause: • Fever • fatigue and lack of energy • Hand-foot syndrome • inflammation of the mouth, esophagus, and • Crab erythema (when high-dose cytarabine throat is combined with continuous infusions of fluo- • bone marrow suppression rouracil) • nausea and anorexia. Fluorouracil With Cytarabine • Diarrhea pyrimidine • Severe cerebellar neurotoxicity • Hair loss analogues, we • Chemical conjunctivitis • Mucositis (when combined with folinic acid) may all win! Drug interactions No significant drug interactions occur with most of the pyrimidine analogues; however, several drug interactions are possible with capecitabine. They include: • fludarabine phosphate • cladribine • mercaptopurine • pentostatin • thioguanine. Pharmacodynamics As with the other antimetabolites, fludarabine, mercaptopurine, and thioguanine first must be converted via phosphorylation (in- troduction to a phosphate) to the nucleotide level to be active.

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This 680 Da peptidomimetic compound had excellent binding affnity but poor oral viability [24] buy discount pilex 60caps line prostate cancer uspstf. In the clinic safe pilex 60caps prostate 4k, single protease inhibitor treatments quickly resulted in drug resistance, so other protease inhibitors were rushed to market (Table 4. Env or “envelope” codes for gp160, which is a precursor to the fusion proteins gp120 and gp41. Regulator of virion (Rev), negative regulatory factor (Nef), and transcriptional AcTivator (Tat) are viral regulatory genes to augment and time expression. This cocktail approach is advantageous because it may be tailored to a given patient’s drug resistances, resulting in viral loads low enough to signifcantly suppress (95%) disease transfer between infected mother to prenatal child [26]. The most attractive design strategies include the development of novel zinc-binding ligands and to exploit alternative ways to increase inhibitory potency by exploring the differences between the various enzyme subtypes [44, 45]. Identifcation of protease secondary binding sites (exosites), that is, nonactive site regions that facilitate or modulate protease activity, could be utilized for the design of selective inhibitors within protease families. Metallo(zinc)-proteases use the nucleophilic attack of a water molecule as one of the steps of amide bond hydrolysis [60]. The tetrahedral intermediate that results from water addition to the amide carbonyl has been the focus of many protease inhibitor designs. These analogs allow the incorporation of specifcity elements for both the S and S′ sub- sites of the enzyme. The triple-helical structure allows for interaction with both the active site and exosites [62]. Triple-helical conformation is also less susceptible to general proteolysis than peptides and other folded proteins [63, 64]. In order to create the desired phosphinate transition state analogs, our laboratory prepared protected Fmoc-phosphinodipeptides [57, 65–67]. Due to the low melting temperature of the potential inhibitor (T ∼ 25 ∘C), K values were frst determined at 10 ∘C. The conformation of insect defensins (132 from Ganz) is distinct, with a prominent α-helical segment that is linked by two disulfde bonds to the C-terminal β-sheet. These cyclic peptides have been purifed from nonhuman primates, and are encoded by mutated α-defensin genes (Figure 4. Retrocyclins are synthetic θ-defensin peptides designed based on the human genome, lacking the premature stop codon present in their natural counterparts. These fndings suggest that postbinding effects, such as in situ oligomerization, may contribute to the antitoxic properties of retrocyclins [84]. The above effects improve the likelihood of the θ-defensin delivery to bacterial intracellular destinations and are supported by radial diffusion assays, in which θ-defensins were shown to be effective against B. Protein kinases catalyze the transfer of the terminal phosphoryl group from Adenosine triphosphate to a protein or peptide substrate (Figure 4. There are at least 500 kinases, and they account for approximately 2% of the human genome [85]. Kinases play an important role in regulating many aspects of cellular func- tion and their dysregulation has been implicated in numerous diseases. Kinases are presently the second most popular drug target, behind G-protein-coupled receptors, comprising 25% of the drug development effort in pharmaceutical companies [86]. Due to this conservation, it has been diffcult to develop small molecule inhibitors exhibiting high selectivity. Although all kinases share these important domains, their substrate specifcity is highly diverse due to varying regulatory sequences outside of these domains [85]. Protein–protein interactions are the major determinants of kinase specifcity and they have been intensely studied in order to develop effective inhibitors. Kinases preferentially bind to specifc recognition motifs within the substrate they phosphory- late. Peptides mimicking these binding sites should have better specifcity than small molecules due to the larger binding surface, thus offering greater opportunity for the development of effective inhibitors (Table 4. This underscores the importance of extensive protein–protein interactions for the inhibition specifcity.