抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

The neuropathic pain triad: neurons, immune cells and glia

The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG I...

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Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology.

Changes of parameters of functions of respiratory and cardiovascular systems of different age rats under influence of small doses of cholinesterase inhibitor Phosphacol

Effect of Bovine Serum Albumin RedoxStatus on Its Interaction with Paraoxon as Determined by Molecular Modeling

Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables, and fruits. Most of them possess antioxidant or anti-inflammatory properties and are claimed to provide protection against many diseases if taken regularly. At the same time, toxicological studies of nutraceuticals have been limited, so the safety of many of them cannot be guaranteed. Animals share many genetic, anatomical, and physiological similarities with humans, and they continue to be widely used in preclinical studies of drugs, in spite of a lack of their validity which is due to the great phenotypic differences. The absence of toxicity in animals provides little probability that adverse reactions will also be absent in humans. There are currently thousands of researchers involved in the development of alternatives to animal use in the life sciences. Statistical machine-learning tools, once developed, might become a powerful means to explain the complex physiological effects of nutraceuticals. The use of different models and algorithms can provide a more scientific basis for risk assessment of nutraceuticals for humans.

Safety and toxicity evaluation of nutraceuticals in animal models.

Publisher Summary
Fluoroorganic compounds attracted the attention of researchers nearly 70 years ago when among a large class of biologically inert chemicals, a group of very toxic compounds was revealed, having the general formula SO2FCOOR and the common name ‘‘fluoroacetate’’ (FA). The extreme toxicity of FA is determined by its similarity to acetate, which has a central role in cell metabolism. The mechanism of toxic action of FA is widely known as ‘‘lethal synthesis.’’ The toxicological effects of FA do not become apparent immediately even after exposure to lethal doses, but after a latent period of half an hour to several hours for animals and humans. A characteristic feature of the clinical picture of intoxication with FA is a latent period of 0.5 to 6 h. A broad variability of clinical manifestations of FA effects in different animal species is one of its characteristic features. Among the after effects that develop after acute intoxication with FA, are various neurological disturbances: impaired muscular tonus and reflex activity, and transient spasmodic and meningeal syndromes. Long after an acute poisoning (from 1.5 to 9 years), a tendency for epileptoid seizures, ataxia, extremity muscular hypertension, spastic tetraplegia, blindness of cortical origin, diffuse brain atrophy, and psychic disorders shows itself. Decades of studies on the toxicology of FA have led scientists to the conclusion that treatment of intoxications can be successful only if timely general and symptomatic therapy is applied, but not specific antidotes.

CHAPTER 13 – Fluoroacetate

The blocker of two-pore channels trans-NED 19 and hydrogen peroxide were found to inhibit histamine-induced relaxation of rat-aorta. The degree of inhibition depended on histamine concentration. The relaxation in response to I μM histamine of rat aorta preconstricted with 30 mM KCI, serotonin, or endothelin- 1, was completely abolished by 30 μM trans-NED 19. On the other hand, trans-NED 19 decreased the relaxation of the aorta in the presence of 10 μM histamine only by 2.1-fold to 2.4-fold, and there was almost no inhibition by trans-NED 19 of the relaxationinduced by 100 ptM histamine.) Relaxation of precontracted with serotonin aorta in response to 10 and 100 μM histamine was reduced by hydrogen peroxide (200 M) by 10- and 2.5-fold, respectively. Suppression of aorta relaxation by trans-NED 19 and H202 correlated with their inhibitory effect on the histamine-induced increase in the cytoplasmic free calcium concentration in human umbilical vein endothelial cells. With the use of a fluorescent probe LysoTracker, the cis-NED19 binding sites were demonstrated to be localized in endolysosomes of the endothelial cells. These data indicate that two-pore calcium channels participate in the histamine-induced endothelium-dependent relaxation of rat aorta. Furthermore, their functional role is exhibited much more clearly at low histamine concentrations. We suggest that hydrogen peroxide evokes depletion of intracellular calcium depots thereby suppressing the response to histamine.

Suppression of Histamine-Induced Relaxation of Rat Aorta and Calcium Signaling in Endothelial Cells by Two-Pore Channel Blocker trans-NED19 and Hydrogen Peroxide.

Nikolay V. Goncharov

Papers

Changes of parameters of functions of respiratory and cardiovascular systems of different age rats under influence of small doses of cholinesterase inhibitor Phosphacol

Effect of Bovine Serum Albumin RedoxStatus on Its Interaction with Paraoxon as Determined by Molecular Modeling

Safety and toxicity evaluation of nutraceuticals in animal models.

CHAPTER 13 – Fluoroacetate

Suppression of Histamine-Induced Relaxation of Rat Aorta and Calcium Signaling in Endothelial Cells by Two-Pore Channel Blocker trans-NED19 and Hydrogen Peroxide.