SARS Virus Treatments

Swine Influenza

Swine Influenza

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Pandemic Shield Ebola Survival Plan

Pandemic Shield is an ultimate preppers guide to outbreaks and how to survive them. You will learn how past pandemics have affected our world and what you can do in case of an outbreak. You can use this clear and precise survival guide to: Prepare for the new plague, know the real truth behind the Ebola pandemic. Get your home ready for lockdown. in case of crisis learn how to prep your home for a pandemic. This extensive survival guide section will show you how to prepare your home for any crisis. what to do if the medical system fails. how to treat illness at home.gathering food and water supplies and first aid preparation among others. You will also discover how you can begin to prepare before it is even too late. with natural immune boosting strategies and ways to prevent illness. The threat of an Ebola outbreak is real and right here on your doorstep. It is only a matter of time before it affects you and those you care about and the authorities are doing nothing about it. With Pandemic Shield you will literally be ready for anything. from disease to social and economical breakdown. Whether or not the Ebola threat becomes a pandemic, this is an urgent reminder that we need to prepare ourselves and our families for any possible disaster.

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Pandemic Survival

This eBook shows you what it takes to survive the next pandemic. There is no doubt that in the future, the world will be hit with a huge pandemic, either from natural causes or from a terrorist attack. As you look through history, you will be hard-pressed to find any pandemic in history that has killed less than 1 million people. You do not want you or your family to be among those millions. And with the help of the information in this eBook, you have a way to survive the global pandemic that will come. Wishing it won't happen doesn't do anything Preparing for it gives you the tools to survive AND thrive. This book contains the two-pronged approach of John Hartman's years of research in figuring out how pandemics work and living through a dangerous flu outbreak. This gives you the methods to both avoid getting a virus in the first place, and how to strengthen your immune system should you come down with a virus. You don't have to lay down and die. You can fight the next pandemic. More here...

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Global Molecular Epidemiology of HIV Understanding the Genesis of AIDS Pandemic

The HIV AIDS pandemic continues to expand globally at a rate of 13,000 new infections everyday. The Joint United Nations Program on HIV AIDS (UNAIDS) estimates that 40.3 (36.7-45.3) million individuals are living with HIV AIDS, and about 25 million patients have already died (UNAIDS WHO, 2005). A total of estimated 65 million individuals have been thus infected with HIV worldwide since the epidemic started a quarter century ago. In 2005 alone, there were 4.9 (4.3-6.6) million new HIV infections and 3.1 (2.8-3.6) million AIDS deaths (UNAIDS WHO, 2005). This could be translated as that 9.3 new infections and 5.9 AIDS deaths occurred every minute (or a new infection every 6-7 sec and an AIDS death every 10 sec) worldwide. Figure 1 illustrates the magnitude of HIV AIDS epidemic in different regions of the world. Heterosexual transmission remains the dominant mode of transmission and accounts for 85 of all HIV infections worldwide. Sub-Saharan Africa is an epicenter of the pandemic and...

Primary Sequence And Metabolic Pathway

Figure 3.1 Superimposed structures of the SARS protease protein obtained from crystallography (light yellow), and a homology model (dark blue). This is typical of a good homology model, in that the largest errors are in loops, while a-helices and b-sheets are reproduced most accurately. A color copy of this figure is contained on the accompanying CD. Figure 3.1 Superimposed structures of the SARS protease protein obtained from crystallography (light yellow), and a homology model (dark blue). This is typical of a good homology model, in that the largest errors are in loops, while a-helices and b-sheets are reproduced most accurately. A color copy of this figure is contained on the accompanying CD.

Historical Perspective of Pharmacology

Receptor-based or biochemical pharmacology-driven drug discovery dominated biomedical research from the late 1950s through the early 1990s. This approach was greatly facilitated by the development of radi-oligand binding assays (Snyder, 2008) that made possible the rapid assessment of structure-activity relationships (SARs). The latter advance was ideal for drug discovery as it required the use of minimal amounts of compound, thereby lowering considerably the cost of screening. Thus, receptor binding assays provided a high-throughput means to iteratively evaluate and optimize NCEs for potency, efficacy, and target selectivity in vitro with incremental advances in throughput as new technologies were developed to automate the process (Comley, 2006). Whereas previously grams of NCE were required to assess initially its therapeutic potential, now 5-10 mg sufficed for this purpose allowing both targeted NCEs and synthetic chemical intermediates to be assessed for target interactions. After...

Methods for Delivery of Morpholinos

Single-stranded unmodified Morpholinos diffuse into some permeable cell types and tissue explants, resulting in experimentally useful cytosolic concentrations without employing any special delivery procedures beyond bathing cells in a solution containing dissolved Morpholinos. Such simple delivery has been reported in dystrophic muscle,65,66 in Ebola virus-infected mice,36 in adult rat liver,67 in the retina of later-stage developing zebrafish,68 in the epithelial cells of the explanted pancreas of the stage E11 through E13 mouse embryo69 and in the explanted liver of the E10 mouse embryo.70 Successful cytosolic delivery in the brain by intracerebroventricular infusion of single-stranded unmodified Morpholinos has been reported.71 However, most cell types do not readily take up bare Morpholinos from solution and so some assistance is required to achieve experimentally useful delivery.

DIGE in the Clinical Setting

Although the potential for DIGE to address clinical studies is only beginning to be addressed for example, see (29,30) , many studies have been published demonstrating the feasibility and benefit of DIGE MS using small patient cohorts for preliminary studies in colon (14), liver (33,34,35), breast (36,37), esophageal (38,39), and pancreatic cancers (40), as well as other important clinical studies such as Severe Acute Respiratory Syndrom (SARS) (41). Many studies also explore the important benefit of procuring samples using laser capture microdissection (LCM - see Chapters 3, 5, and 9 by Diaz et al., Zhang et al., and Mustafa et al., respectively) for a highly enriched population of the cells under study (16,30,42,43,44). These LCM studies necessitate the use of the saturation chemistry owing to the increased sensitivity but limited multiplexing power, and typically require secondary preparative gels with higher protein loads to enable protein identification by MS.

New Reboxetine Analogues

New derivatives of 2- (phenoxy)(phenyl)-methyl morpholine 98 have been disclosed as inhibitors of monoamine reuptake by Fish et al. at Pfizer 82 . SARs established that serotonin and noradrenaline reuptake inhibition were functions of stereochemistry and aryl aryloxy ring substitution. Consequently, selective NRIs, SSRIs and dual SNRIs were all identified (Fig. 33, Table 17).


Kozikowski et al. at the University of Illinois at Chicago have reported further SARs in a series of 4-(4-chlorophenyl)piperidine analogues each bearing a thioacetamide group at C-3 (117) 96 . The paper describes a comprehensive analysis of the influence of relative and absolute stereochemistry at C-3 and C-4 of the piperidine ring on inhibition of the NA, 5-HT and DA transporters (Fig. 38). tivity compared to the corresponding sec-amines, and ferf-amines were generally weaker SRIs compared to sec-amines. No compound demonstrated any significant DRI activity. The combination of these SARs resulted in ferf-amines yielding the most potent NRIs with better selectivity for SRI and DRI.

The Use of GADriven Evolutionary Experiments

As shown above, GAs are rather tolerant to experimental errors and may still yield good re suits even if the starting hypothesis is wrong. This behavior is especially true for false nega tive results, since these are simply eliminated in the selection step and are not remembered The elimination of misleading false positive results takes somewhat longer - depending or, how often a good chromosome is allowed to replicate. This fuzzy and robust optimization property makes GAs especially attractive for real time experimental optimizations as described above. Furthermore, for the application of GA-based evolutionary methods, similar to Nature, one does not need to know or to describe chemical structures explicitly, or to develop a structure-based hypothesis about SARs.

Historical perspective

As medicinal chemistry developed into a more rational discipline, it became more important to measure the intrinsic activities of compounds independent of their pharmacokinetic parameters. The measurement of intrinsic efficacies was essential for rationalizing structure-activity relationships (SARs), a foundation of modern drug discovery. These drivers led to the development of a variety of assay models that employed isolated organ tissues to study drug action. Such in vitro approaches dramatically advanced our knowledge of the pharmacological basis of drug action 2 . In many instances, the correlation between smooth muscle responses and efficacy in humans was remarkable. Examples include the guinea pig ileum as a model for narcotic analgesia 3,4 and vascular smooth muscle strips as a model for hypotensive agents 5,6 . While these approaches allowed measurement of the intrinsic efficacy of drugs apart from their pharmacokinetic attributes, they were quite laborious. In most assays, a...

Objective and Rationale

To confirm the hits from HTS and generate SARs for compounds from medicinal chemistry, a secondary heterogeneous binding assay was developed. This assay used the dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) technology based on time-resolved fluorescence (TRF) lanthanide chemistry. The europium label was detected by excitation at 340 nm and emission at 615 nm. The resulting long-lived fluorescence signal allowed for delayed detection of emission signals, which reduced auto-fluorescence backgrounds and thereby increased overall assay sensitivity. The current assay method (Figure 5.2A) employed the europium-labeled Eu-anti-His antibody. The assay measured the ability of Hsp90 inhibitors to complete the binding of the biotin-radicicol to the ATP-binding pocket, and was used to determine IC50 values and SARs of small molecule Hsp90 compounds.

Zidovudine Retrovir

During the early 1980s, when the medical community realized the potential of HIV AIDS to become a pandemic, research to find effective anti-HIV medications intensified. AZT, first synthesized in 1964 as an anticancer agent, was found to be an effective drug against HIV and shown to prolong the life of patients with AIDS.1 It was first approved in 1987 for the treatment of, and later, for the prevention of HIV infections (e.g., mother-to-child transmission or exposure to the virus).

Structure Activity Relationship

Based on whole cell biological activity, SARs could be deduced, with aromatic groups at N(1) and C(5) and a methyl group at C(2) as essential features (Fig. 33). Additionally, methylene-linked thiomorpholine or N-methylpiperazine substituents at C(3) act as hydrogen bond acceptors to improve activity (Fig. 34 22b-g) 316, 317 . Thus, a 1,2,3,5-tetrasubstituted pyrrole is the pharmacophore essential for antitubercular activity (Fig. 32). The 2-methyl group is not involved in any phar-macophoric interaction but influences the conformation of the substituents at positions 1 and 3 of the pyrrole ring 316, 317 .

Mundus Vult Decipi High Mutation Rates of HIV and New Paradigms for Treatment

Insight into the latest development of bio-pharmaceuticals against cancer is followed by the latest therapies against HIV-1, which is the causative agent of AIDS. The first cases were reported in 1981 already and Robert Gallo (who discovered the virus two years later) talked about a hybris, because medical scientists claimed that they would have previously eradicated infectious diseases - at least in the wealthy regions of the industrialized world. But this virus is currently spread worldwide and affects millions of individuals the present situation is especially critical in sub-Sahar-an countries (roughly 70 of the world cases), where the virus affects more than 30 million people. Altogether the global AIDS pandemic has killed more than 28 million people so far and infected more than 42 million - it is estimated that 45 million new cases of HIV infections will occur by 2010. The impact of this virus in health and social relationships has been tremendous in many countries around the...

Computers as Drug Design Aids

When this era came to an end, most of the easy stuff' had been done. Then, what became known as rational drug design made its debut on the drug scene. Theories of drug action mechanisms began to apply ideas and facts from tangential disciplines such as physical organic, and biochemistry. Their tools changed armchair SARs to quantitative SARs. Physics lent medicinal chemists some of its tools, which had magnificent applications by allowing us to see our small molecules. Among these tools were spectroscopies with first names such as IR, NMR, ESR, and MS. As those began to improve in terms of sensitivity, resolution, and speed chemists must have begun to feel somewhat like astronomers peering further and further into the molecular and atomic universe. A quantum leap for medicinal chemistry was the introduction of X-ray crystallography. At first a cumbersome tool whose results were mathematically burdensome to evaluate, it had helped to resolve some pesky structural problems as far back...

Refine Model Structure

Physiological parameters can be found in the biomedical literature, and they were recently compiled by Brown et al. (1997). Partition coefficients can be measured by equilibrating tissue homogenates in a vial with an atmosphere containing the test chemical (Sato and Nakajima 1979a Gargas et al. 1989). Constants for metabolism (enzyme kinetic constants for saturable, firstorder or second-order reactions) can be determined in vitro with tissue homogenates, microsomal preparations, liver slices, and so on, by supplementing these preparations with reactants to promote metabolic reactions (Sato and Nakajima 1979b Hilderbrand et al. 1981 Kedderis et al. 1993). Another method for assessing metabolic parameters in vivo relies on closed chamber inhalation techniques. Here, a small numbers of live animals are placed in a closed chamber to measure the rate of loss of chemical at a variety of chamber concentrations (Hefner et al. 1975 Filser and Bolt 1979 Gargas...

Why C-6 Deoxy Tetracyclines Are More Stable

The large amount of research carried out to prepare semisynthetic modifications of the tetracyclines and to obtain individual compounds by total synthesis revealed several interesting SARs. Reviews are available that discuss SARs among the tetracyclines in detail,161-163 their molecular and clinical properties,164 and their synthesis and chemical prop-erties.162,163,165,166 Only a brief review of the salient structure-activity features is presented here. All derivatives containing fewer than four rings are inactive or nearly inactive. The simplest tetracycline derivative that retains the characteristic broad-spectrum activity associated with this antibiotic class is 6-demethyl-6-deoxytetracycline. Many of the precise structural features present in this molecule must remain unmodified for derivatives to retain activity. The integrity of substituents at carbon atoms 1, 2, 3, 4, 10, 11, 11a, and 12, representing the hydrophilic southern and eastern faces of the molecule, cannot be...

Methine Butyrophenone

SARs of butyrophenones have some unusual features that sometimes do not seem to conform to many of our empirical rules. The 4-F atom on the benzoyl portion of the molecule seems mandatory for optimum activity. When combined with 1-phenyltriazospiro group as in the spiperones, it achieves extreme potencies. Absence of substitution on the benzoyl ring or substituents other than F, especially at the 2 or 3 positions, diminishes activity considerably. Isosteric substitutions, such as thiophene for benzene, are also not useful. The following series illustrates the diminution of activity. It is particularly surprising how much inferior the CI atom is to F.

An Agent Possessing Both An Indolethylamine And A Phenylethylamine Moiety

Tetrahydrocannabinoid is a depressant with apparent stimulant sensations arising from depression of higher centers. Many effects, reputedly subjectively construed as pleasant, are evident at low doses. The interested reader may consult a pharmacology text for a detailed account. At higher doses, psychotomimetic actions, including dysphoria, hallucinations, and paranoia, can be marked. Structural features associated with activity among cannabis-derived compounds have been reviewed.42 Notably, the phenolic OH is required for activity. Certain SARs (especially separation of potency between enantiomers) for cannabinoids suggested action at receptors.43 Two receptors for THC have been discovered. The relevant receptor for CNS actions is CB1.44 CB2 occurs in immune tissues. The first natural ligand found for the receptor is the amide derivative of arachidonic acid, anandamide.45 Other natural cannabinoids are arachidonic acid 2-glycerol ester and 2-arachidonyl glycerol ether.46 The...

Qualitative vs Quantitative Pharmacophore Models

Notably, the obtained quantitative models are somewhat different from qualitative ones, as produced by the Catalyst module HipHop 27 while the qualitative model seeks to find common features present in all models of the training set, the quantitative method looks primarily for those features that can explain the high affinity of the most active compounds, and which are not present in the lesser active ones. Often publications report the use of structurally closely related compounds for the generation of quantitative pharmaco-phore models. This may be largely because during optimization of initial lead structures, where this method is preferentially applied, medicinal chemists usually work on a distinct chemical class of compounds. A qualitative model based on highly similar compounds identifies all those features that were not changed (for whatever reason) as being equally important for the binding, and therefore often identifies also structurally quite similar compounds in a database...

Structureactivity Relationships

Pharmacophore Thylamine

The structure-activity relationships (SARs) summary is shown in Figure 16.11. Comprehensive reviews of the SARs of a- and -agonists and antagonists33-35 covered their developments in the late 1980s. The parent structure with the features in common for many of the adrenergic drugs is -phenylethylamine. The manner in which -phenylethylamine is substituted on the meta- and para-positions of the aromatic ring, on the amino (R1), and on a-, (R2)-, and -positions of the ethylamine side chain influences not only their mechanism of action, the receptor selectivity, but also their absorption, oral activity, metabolism, degradation, and thus duration of action (DOA). For the direct-acting sympathomimetic amines, maximal activity is seen in -phenylethylamine derivatives containing (a) a catechol and (b) a (1 )-OH group on the ethylamine portion of the molecule. Such structural features are seen in the prototypical direct-acting compounds NE, E, and ISO. The SARs are supported by the model of...

Quazepam t12 39 longacting

Chlordiazepoxide Metabolites

Lorazepam, (Ativan), is the 2'-chloro derivative of oxazepam. In keeping with overall SARs, the 2'-chloro substituent increases activity. As with oxazepam, metabolism is relatively rapid and uncomplicated because of the 3-hydroxyl group in the compound. Thus, it also has short half-life (2-6 hours) and similar pharmacological activity.

The Antitussive Action Of Opioids Blockade Of Cough Reflex

Cough Receptors

Each cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors. There is evidence, primarily clinical, that the sensory limb of the reflex exists in and outside of the lower respiratory tract. Although myelinated, rapidly adapting pulmonary stretch receptors (RARs), also known as irritant receptors, are the most likely type of sensory nerve that stimulates the cough center in the brain, afferent C-fibers and slowly adapting pulmonary stretch receptors (SARs) also may modulate cough. RARS, C-fibers, and SARs have been identified in the distal esophageal mucosa however, studies have not been performed to determine whether they can participate in the cough reflex. Although gastroesophageal reflux disease can potentially stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract without aspiration and by irritating the lower respiratory tract by micro- or macroaspiration, there is evidence that...

O Proteins And Proteinlike Compounds

The chemistry of proteins is complex, with many facets not completely understood. Protein structure is usually studied in basic organic chemistry and, to a greater extent, in biochemistry, but for the purposes of this chapter, some of the more important topics are summarized, with emphasis on relationships to medicinal chemistry. Much progress has been made in understanding the more sophisticated features of protein structure4 and its correlation with physicochemical and biological properties. With the total synthesis of ribonu-clease in 1969, new approaches to the study of SARs among proteins have involved the synthesis of modified proteins.

The Structure of the Search Space

Obviously one would use different selection methods if dealing with a unimodal (Chapter 8, Figure 8.4a) or multimodal (Chapter 8, Figure 8.4b) SAR. But what do real SARs look like Interestingly, this important question is still very much open to discussion in the community of medicinal chemists, mainly because very little knowledge is available about large SAR landscapes. Thus, we decided to get an impression of the problem by synthesizing a complete library of 256 chemically similar molecules of inhibitors that are biased towards the serine protease thrombin using the known Ugi-type four-component reaction. For this library four different aldehydes (A1-A4), amines (B1-B4), isonitriles (C1-C4), and carboxylic acids Current descriptions of SARs, and also Figure 9.2, often wrongly suggest that the chemistry space by itself is smooth or continuous . It is important to understand that the space of possible molecules is discrete - each molecule is an assembly either of discrete atoms, or,...

Summary Of Structureactivity Relationships

The extensive investigations of SARs in the morphine series have highlighted the fact that although nitrogen is probably the primary pharmacophore for receptor binding, the subsequent zipper attachment of ligand to receptor and responses elicited depend heavily upon secondary perturbations. The aromatic ring, although not essential for opioid responses, as 220 has demonstrated, is necessary in most opiates and its binding is augmented by a free 3-OH group. But it is the influence of the conformation and substituent effects of the C-ring that are perhaps the most intriguing, and it is their exploration that may lead to a better understanding of the nature of multiple opioid receptors.

Antiviral Agents 6121 Viral Diseases

The structure of the viral particle (viron) provides the basis for the treatment of viral infections. The virus 6.53 comprises a central core of nucleic acid material (either DNA or RNA), protein containing the polymerase enzyme involved in viral replication, a protein coat and the surface glycoprotein. The latter, comprising a haemagglutinin and a neuraminidase, are involved in the recognition and interaction between the virus and its host cell. In the various strains of the 'flu virus', there are up to 15 different types of haemagglutinin and nine different neuraminidases. Thus, the Asian flu strain of 1957 was the H2N2 strain, while the avian flu strain which is currently of concern is H5N1.

Viral and Bacterial Infections

The recently emerged severe acute respiratory syndrome (SARS) coronavirus has shown the threat of worldwide pandemic and demonstrated the need for antiviral therapies. R9F2C PPMOs targeting a conserved region of SARS-CoV isolates, the transcription-regulatory sequence (TRS) in the 5'-UTR, was the most effective PPMO found. Treatment with the PPMO reduced cytopathic effects, knocked down viral titers to background levels and halted the spread of the virus, with no new plaques formed. The conjugate was effective if administered at any time before peak viral synthesis. A resistance study to assess the development of viral resistance to submaximal doses of the PPMO that targeted the TRS transcript found that some increases in viral titer had developed, which indicates partial viral resistance to the TRS2 PPMO. However, the partially resistant virus grew more slowly and formed smaller plaques than the wild-type virus.102 Ebola virus. Ebola virus causes severe hemorrhage fever...

General Discussions

Regional differences and the potential of unknown infective agents must be included in any discussions of the future prospect of blood substitutes. Also to be included is the degree of regulatory requirements. Blood substitutes are urgently needed in regions of the world where there are severe shortages of donor blood because of cultural or religious beliefs that cause people to be less willing to donate blood. They are also urgently needed in regions with higher incidences of infective agents like HIV and thus a higher potential for contaminated donor blood. It is less urgent in regions with a lower incidence of HIV and where costly screening tests are being used to screen out infective agents in donated blood. On the other hand, it is important to remember the past unexpected outbreaks of HIV and hepatitis C and the resulting contaminated donated blood that persisted for years until proper screening tests are developed. If this should happen again with some yet unknown agents, (e.g....


Morpholinos targeted to various sites in the RNA of the Ebola virus have been tested at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRID) for efficacy in cell culture, mouse, guinea pig and Rhesus Macaque models. Some targets were effective in rodents in both prophylactic and post-exposure treatments, and after prophylactic treatment 75 of Rhesus Macaques survived Ebola infection.36 In 2004, the US Dept. of Defense requested AVI BioPharma Inc. to synthesize Morpholinos for the emergency treatment of a scientist exposed to Ebola at USAMRIID. However, no infection developed and so the delivered Morpholinos were not administered.37

The Future

In the anti-infective area, increase in resistance to established antibiotics will require that new drugs be developed. The HIV pandemic and resulting AIDS syndrome have opened the door to a host of opportunistic infections. Exacerbated by HIV, tuberculosis is having a savage effect on the lives of millions of people, and new drugs are needed to combat resistant strains (Zhang et al., 1992). The incidence of malaria is increasing (Brown, 1992) and we badly need a new generation of drugs for this disease. We still have no drug at all to treat the common cold, and only a poor and limited therapy for influenza. Macromolecular targets have already been identified for all these diseases.


The TAR RNA hairpin structure in the 5'R is important for optimal transcription from the viral promoter that is located within the 5' long terminal repeat (LTR). However, it is also possible that the 3' LTR of an integrated provirus is transcriptionally active in a TAR-dependent manner, thereby triggering the expression of downstream cellular genes (Klaver and Berkhout, 1994c Raineri and Senn, 1992 Greger et al., 1998). A detailed TAR phylogeny has been presented previously for all human and simian immunodeficiency virus groups (HIV and SIV) (Berkhout, 1992). For instance, viruses that belong to the HIV-2 group and several SIV groups contain a relatively complicated, branched stem-loop structure as the TAR element compared with the one-stem structure of HIV-1. An updated TAR phylogeny is presented in Fig. 3, which includes the HIV-1 subtypes of the major group M. The group M viruses that comprise the current global pandemic have diversified during their spread worldwide. These...

Select Applications

FAC-MS has been used recently in antiviral development projects to discover two small molecule natural products inhibiting the entry of SARS-Coronavirus into Vero-E6 cells 26 . A range of Chinese herbs (121 different species) were extracted in 85 ethanol and screened via online FAC-MS (using an electrospray TOF instrument), through a column containing the SARS S2 protein. The authors estimate that 130 compounds with Kds under 10 mM were discovered by FAC-MS, and of these hits, two molecules (luteolin and tetra-O-galloyl-b-D-glucose) exhibited low micromolar EC50s in an infection assay using a pseudo-typed virus, correlating well with their highest binding strength in the FAC assay. These two molecules exhibit an activity far superior to glycyrrhizin, another small molecule recently reported to exhibit antiSARS-CoV activity 36 .

Therapeutic Uses

Amantadine and rimantadine are effective for the prevention and treatment of influenza A virus infections. Seasonal prophylaxis with either drug (a total of 200 mg day in one or two divided doses in young adults) is 70-90 protective against influenza A illness. Efficacy has been shown during pandemic influenza, in preventing nosocomial influenza, and in curtailing nosocomial outbreaks. Doses of 100 mg day are better tolerated yet still protective against influenza. Postexposure prophylaxis with either drug provides protection of exposed family contacts if ill young children are not concurrently treated.


Angiotensin II is the most active form hence, it is the most investigated angiotensin for pharmacological action and SARs. The two primary actions of angiotensin II are vasoconstriction and stimulation of synthesis and secretion of aldosterone by the adrenal cortex. Both of these actions lead to hypertension.


The most severe influenza pandemic was the Spanish flu in 1918-1919, which caused the deaths of at least 20 million people. The pathogenicity of influenza virus is high 154, 155 . Almost a quarter of a million patients with flu are hospitalised every year in the United States. About 62 million people are expected to die worldwide, when a new type of pandemic flu strikes. On the surface of influenza A viruses, two unique glycoproteins are localised, namely, HA and neuraminidase (NA). These glycoproteins play a decisive role in infection and replication. To avoid the first contact of the virus and a host cell, the first approach has focused on HAs, which participate in infection of influenza virus to host cells. HAs of influenza A viruses bind to a specific receptor -sialyl lactose (Neu5Ac-a-(2 3)-Gal-P-(1 4)-Glc). This event starts the adhesion of influenza viruses to the surface of the host cell 154, 155 . Dendrimers with sialic acid as synthetic inhibitors of influenza virus have...

Antipedicular Agents

Midazolam Imidazole Ring

Scabicides (antiscabious agents) are compounds used to control the mite Sarcoptes scabiei, an organism that thrives under conditions of poor personal hygiene. The incidence of scabies is believed to be increasing in the United States and worldwide and has, in fact, reached pandemic proportions.99 Pediculicides (antipedicular agents) are used to eliminate head, body, and crab lice. Ideal scabi-cides and pediculicides must kill the adult parasites and destroy their eggs.


Global dissemination of HIVs represents a dramatic and deadly example of recent genome emergence and expansion. As reviewed in this chapter, recent studies revealed that a pandemic HIV strain, HIV-1 group M, began its expansion in human population roughly 70 years ago (early twentieth century), it has been diversifying rapidly, now comprising a number of different subtypes and CRFs, and that new recombinant strains are arising continually, becoming a powerful force in global HIV-1 spread. Studies also provide information to delineate the mechanism of viral evolution and for the studies on biological features of HIV strains related to pathogenecity and disease progression. However, the biological significance of the global diversity of HIV-1 strains remains to be defined. Although the immune correlates for protection are still incompletely understood, the extensive variation of HIVs could probably be important in the formulation of the vaccine immunogens. In conclusion, molecular...

Meropenem metabolite

To date, the more useful semisynthetic modifications of the basic 7-ACA nucleus have resulted from acylations of the 7-amino group with different acids or nucleophilic substitution or reduction of the acetoxyl group. Structure-activity relationships (SARs) among the cephalosporins appear to parallel those among the penicillins insofar as the acyl group is concerned. The presence of an allylic acetoxyl function in the 3-position, however, provides a reactive site at which various 7-acylaminocephalosporanic acid structures can easily be varied by nucleophilic displacement reactions. Reduction of the 3-acetoxymethyl to a 3-methyl substituent to prepare 7-aminodesacetylcephalosporanic acid (7-ADCA)

O Antipsychotics

Sar Phenothiazine

Horn and Snyder,29 from x-ray crystallography, proposed that the chlorine-substituted ring of chlorpromazine base could be superimposed on the aromatic ring of DA base, with the sulfur atom aligned with the -hydroxyl group of DA and the aliphatic amino groups of the two compounds also aligned. The model used here is based on the interpretation of the SARs by Gordon et al.28 and on the Horn and Snyder29 proposal but involves the protonated species rather than the free base. The effect of the substituent at the 1-position might be to interfere with the side chain's ability to bring the protonated amino group in proximity with the 2-substituent. In the Horn and Snyder29 scheme, the sulfur atom at position 5 is in a position analogous to the -hydroxyl group of DA, and it was also assigned a receptor-binding function by Gordon et al.28 A substituent at position 4 might interfere with receptor binding by the sulfur atom.

Oseltamivir Tamiflu

Oseltamivir, a second-generation oral neuramidinase inhibitor, is widely used for the treatment and prevention of influenza A and B viral infections, including avian flu. Influenza is a serious respiratory illness that affects millions of people annually ( seasonal flu ) and results in many deaths as well as an estimated 10 billion in lost productivity. The symptoms of flu and the common cold are similar, but flu symptoms are generally more severe. Older people and those with a weakened immune system are especially at risk to develop complications such as bronchitis and pneumonia which are the main causes of influenza-related deaths. In recent years a more virulent influenza A type virus, the avian flu, has emerged. Certain strains of the avian flu (e.g., H5N1) are able to infect humans and cause high mortality. Since the effective treatment of the various flu infections has traditionally been difficult due to the lack of potent antiviral drugs, the possibility of a catastrophic...

Newer Tetracyclines

The remarkably broad spectrum of antimicrobial activity of the tetracyclines notwithstanding, the widespread emergence of bacterial genes and plasmids encoding tetracy-cline resistance has increasingly imposed limitations on the clinical applications of this antibiotic class in recent years.164 This situation has prompted researchers at Lederle Laboratories to reinvestigate SARs of tetracy-clines substituted in the aromatic (D) ring in an effort to discover analogs that might be effective against resistant strains. As a result of these efforts, the glycylcyclines, a class of 9-dimethylglycylamino-(DMG)-substituted tetracyclines exemplified by DMG-minocycline (DMG-MINO), and DMG-6-methyl-6-deoxytetracycline (DMG-DMDOT) were discovered.187-189

Undecylenic Acid

For RNA viruses, replication in the host cell relies either on enzymes in the virion (the whole infective viral particle) to synthesize its mRNA or on the viral RNA serving as its own mRNA. The mRNA is translated into various viral proteins, including RNA polymerase, which directs the synthesis of more viral mRNA and genomic RNA (Figure 49-1B). Most RNA viruses complete their replication in the cytoplasm, but some, such as influenza, are transcribed in the host cell nucleus. RNA viruses include rubella virus (German measles), rhabdoviruses (rabies), picornaviruses (poliomyelitis, meningitis, colds, hepatitis A), arenaviruses (meningitis, Lassa fever), flaviviruses (West Nile meningoencephalitis, yellow fever, hepatitis C), orthomyxoviruses (influenza), paramyxoviruses (measles, mumps), and coronaviruses (colds, severe acute respiratory syndrome SARS ).


For details of the chemistry and SARs of the BZDs, see the discussion of anxiolytic sedative-hypnotic drugs. Among the current clinically useful drugs, the structural features associated with anticonvulsant activity are identical with those associated with anxiolytic sedative-hypnotic activity.

Drug Resistance

It is probably a relatively recent recognition that one of the great factors in shaping human history has been infectious disease. Almost whole populations may have disappeared from the map. Bubonic plague killed one-third of Europe's population in the fourteenth century. The first documented pandemic was in the early sixth century. It began in northeast Africa (Egypt and Ethiopia) and spread through Europe. It lasted 60 years and is estimated to have killed 100 million people. Smaller epidemics continued up to the end of the nineteenth century.


Its primary action is inhibiting the release of GH from the pituitary gland. Somatostatin also suppresses the release of both insulin and glucagon. It causes a decrease in both cAMP levels and adenylate cyclase activity. It also inhibits calcium ion influx into the pituitary cells and suppresses glucose-induced pancreatic insulin secretion by activating and deactivating potassium ion and calcium ion permeability, respectively. The chemistry, SARs, and potential clinical applications have been reviewed.22,31

Chapter Overview

Protein chemistry, essential in understanding the mechanisms of molecular biology and how cellular components participate in physiology, is also key to certain aspects of medicinal chemistry. An examination of the chemical nature of proteins explains the action of those medicinal agents that are proteins, or proteinlike compounds, and elucidates their physicochemical and biochemical properties. This, in turn, relates to their mechanisms of action. Furthermore, in medicinal chemistry, drug-receptor interactions are directly related to structure-activity relationships (SARs) and aid in the process of rational drug design. Drug receptors are considered to be macromolecules, some of which appear to be proteins or proteinlike.


A large number of DA agonists have been synthesized and their DA-ergic activity has been evaluated regarding comparative potency, types of receptor affinity (DAI, DA2, autoreceptor), and SARs, including stereochemical factors. The types of structures involved in these studies are depicted in Figure 12-2. Note that incorporating the phenethyl moiety into the framework of ring systems produces semirigid analogs of DA (e.g., the aminotetralins, ATN). The benzoquinolines also offer semirigid position isomerism octahydrobenzo g quinolines and octahydrobenzo f quinolines each in turn also exhibits cis-trans isomerism, depending on ring fusion geometry. It will be recalled (Chapter 9) that apomorphine (APO) has been shown to mimic DA activity in the CNS and has since been reviewed as a prototype for potential SAR development. The ATNs are particularly interesting. Their synthesis as potential DA agonists in a systematic manner received impetus by a suggestion that the DA pharmacophore within...

Hit Optimization

Depending on the stage of the hit optimization process, the experiments should provide structural information of different qualities. Whereas at the beginning, even crude SARs are sufficient, more detailed information is required at an advanced stage of drug development. Therefore, the techniques change from lig-and- to target-based methods and more complex pulse sequences are applied. Target-based techniques have the additional advantage of offering the possibility of monitoring high-affinity ligands, as low-affinity binders are of minor interest at this stage. Of course, the target needs to be NMR accessible, which sets some limitations in size.

The Kreceptor

The structure of some K-agonists and an antagonist can be seen in Figure 24.5.46,47 TRK-820 is a K-agonist displaying approximately 15 times selectivity toward K-receptors versus -receptors.46 The 4,5-epoxymorphinan structure of TRK-820 is proposed to mimic the tyrosine-glycine moiety of endogenous opioid peptides, in effect the agonist message. The additional 6 -substituent constitutes the address directing the compound to the K-receptor. Spiradoline was one of the earliest compounds to show improved K-receptor selectivity (125 times over -receptors). SARs on this class of compounds revealed that methyl-substituted nitrogen amides, a methylene spacer between the amide and