The exploitation of natural particulates, such as pathogens and mammalian cells, for drug delivery applications is a rapidly emerging field. Here, Yoo and colleagues discuss recent advances in the design of drug carriers based on natural particulates, provide an overview of their current development status and highlight the various applications and limitations of each approach.

Bio-inspired, bioengineered and biomimetic drug delivery carriers

The inhibitory effects of polyanionic substances on the replication of herpes simplex virus (HSV) and other viruses were reported almost four decades ago. However, these observations did not generate much interest, because the antiviral action of the compounds was considered to be largely nonspecific. Shortly after the identification of human immunodeficiency virus (HIV) as the causative agent of the acquired immune deficiency syndrome (AIDS) in 1984, heparin and other sulfated polysaccharides were found to be potent and selective inhibitors of HIV 1 replication in cell culture. Since 1988, the activity spectrum of the sulfated polysaccharides has been shown to extend to various enveloped viruses, including viruses that emerge as opportunistic pathogens (e.g., herpes simplex virus [HSV] and cytomegalovirus [CMV]) in immunosuppressed (e.g., AIDS) patients. As potential anti-HIV drug candidates, sulfated polysaccharides offer a number of promising features. They are able to block HIV replication in cell culture at concentrations as low as 0.1 to 0.01 mu g ml(-1) without toxicity to the host cells at concentrations up to 2.5 mg ml(-1). We noted that some polysulfates show a differential inhibitory activity against different HIV strains, suggesting that marked differences exist in the tar get molecules with which polysulfates interact, They not only inhibit the cytopathic effect of HIV, but also prevent HIV induced syncytium (giant cell) formation. Furthermore, experiments carried out with dextran sulfate samples of increasing molecular weight and with sulfated cyclodextrins of different degrees of sulfation have shown that antiviral activity increases with increasing molecular weight and degree of sulfation. A sugar backbone is not strictly needed for the anti-HIV activity of polysulfates because sulfated polymers composed of a carbon-carbon backbone have also proved to be highly efficient anti-HIV agents in vitro. Other, yet to be defined, structural features may also play an important role. Sulfated polysaccharides may act synergistically with other anti-HIV drugs (e.g., azidothymidine [AZT]). They are known to lead very slowly to virus drug resistance development and they show activity against HIV mutants that have become resistant to reverse transcriptase inhibitors, such as AZT, tetrahydro-imidazo [4,5,1-jk] [1,4] benzodiazepin 2 (1H) thione (TIBO) and others. From studies on their mechanism of action we concluded that polysulfates exert their anti-HIV activity by shielding off the positively charged sites in the V3 loop of the viral envelope glycoprotein (gp120). The V3 loop is necessary for virus attachment to cell surface heparan sulfate, a primary binding site, before more specific binding occurs to the CD4 receptor of CD4(+) cells. This general mechanism also explains the broad antiviral activity of polysulfates against enveloped viruses. Variations in the viral envelope glycoprotein region may result in differences in the susceptibility of different enveloped viruses to compounds that interact with their envelope glycoproteins. The efficacy of polysulfates in the therapy and/or prophylaxis of retroviral infections and opportunistic infections remains to be demonstrated both in animal models and humans. It is important to consider not only treatment of patients who are already infected with HIV, but also prophylaxis and protection from HIV and/or other virus infections. Because (i) sexual transmission is responsible for the large majority of HIV infections worldwide; (ii) this transmission is mostly mediated via mononuclear cells that infect epithelial cells of the genital tract; and because (iii) polysulfates effectively inhibit cell-cell adhesion, polysulfates may be considered as potentially effective in a vaginal formulation to protect against HIV infection. (C) 1997 Elsevier Science Inc.

Sulfated Polysaccharides Extracted from Sea Algae as Potential Antiviral Drugs

Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes.

Integral membrane G protein-coupled receptors (GPCRs) compose the single most prolific class of drug targets, yet significant functional and structural questions remain unanswered for this superfam...

Functional reconstitution of β2-adrenergic receptors utilizing self-assembling Nanodisc technology

This map is an update of the edition 9 map by Berlyn et al. (M. K. B. Berlyn, K. B. Low, and K. E. Rudd, p. 1715–1902, in F. C. Neidhardt et al., ed., Escherichia coli and Salmonella: cellular and molecular biology, 2nd ed., vol. 2, 1996). It uses coordinates established by the completed sequence, expressed as 100 minutes for the entire circular map, and adds new genes discovered and established since 1996 and eliminates those shown to correspond to other known genes. The latter are included as synonyms. An alphabetical list of genes showing map location, synonyms, the protein or RNA product of the gene, phenotypes of mutants, and reference citations is provided. In addition to genes known to correspond to gene sequences, other genes, often older, that are described by phenotype and older mapping techniques and that have not been correlated with sequences are included.

/pdf/linkage-map-of-escherichia-coli-k-12-edition-10-the-4xep962ryl.pdf

Linkage Map of Escherichia coli K-12, Edition 10: The Traditional Map

Molecular interaction between HIV-1 major envelope glycoprotein and dextran sulfate.

We have previously reported the detection of anti-CD4 autoantibodies in the sera of approximately 10% of HIV-1-infected patients. These antibodies recognized epitopes located on the V3V4 domains of the soluble recombinant CD4 molecule but did not recognize CD4 in its native conformation on the cell membrane. To analyse further the biological properties of these antibodies, we have purified them from the sera of six patients using affinity chromatography. We demonstrate that purified and concentrated anti-CD4 antibodies still cannot recognize CD4 either in its native conformation or after the binding of HIV gp120. They also cannot mediate antibody-dependent cellular cytotoxicity on CD4+ or HIV-coated CD4+ cells. In one patient, however, we could detect a minor fraction of anti-CD4 antibodies directed to the V1V2 domains of CD4.

Biological properties of anti-CD4 autoantibodies purified from HIV-infected patients.

Reconstitution of membrane proteins allows their study in a membrane environment that can be manipulated at will Because membrane proteins have diverse biophysical properties, reconstitution methods have so far been developed for individual proteins on an ad hoc basis We developed a postinsertion reconstitution method for CCR5, a G protein coupled receptor, with seven transmembrane α helices and small ecto- and endodomains A His6-tagged version of CCR5 was expressed in mammalian cells, purified using the detergent N-dodecyl-β-d-maltoside (DDM) and reconstituted into preformed liposomal membranes saturated with DDM, removing the detergent with hydrophobic polystyrene beads We then attempted to incorporate CD4, a protein with a single transmembrane helix and a large hydrophilic ectodomain into liposomal membranes, together with CCR5 Surprisingly, reconstitution of this protein was also achieved by the method Both proteins were found to be present together in individual liposomes The reconstituted CCR5 was recognized by several monoclonal antibodies, recognized its natural ligand, and CD4 bound a soluble form of gp120, a subunit of the HIV fusion protein that uses CD4 as a receptor Moreover, cells expressing the entire fusion protein of HIV bound to the liposomes, indicating that the proteins were intact and that most of them were oriented right side out Thus, functional coreconstitution of two widely different proteins can be achieved by this method, suggesting that it might be useful for other proteins

Functional reconstitution of the HIV receptors CCR5 and CD4 in liposomes.

The binding of the human immunodeficiency virus envelope glycoprotein gp120 to the CD4 molecule is the initial step in the viral replicative cycle. This interaction is therefore an important target for therapeutic intervention for the treatment of human immunodeficiency virus infection. We designed an enzyme-linked immunosorbent assay which detects the interaction between recombinant soluble forms of CD4 and gp160. This assay could be used as an initial screen of libraries of synthetic chemical compounds and natural products.

Simple assay to screen for inhibitors of interaction between the human immunodeficiency virus envelope glycoprotein and its cellular receptor, CD4.

Photosensitized UVA light induction of the SOS response in Escherichia coli

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