Molecular Modeling Design Strategy on Novel Drugs for HIV-1 Tat/TAR Complex

Abstract

Glucocorticoids are a widely used class of anti-inflammatory and immunosuppressive drugs, but their therapeutic use is limited by endocrine and metabolic side effects that they produce when given systemically. Since cells of monocyte/macrophage lineage play an important role in the pathogenesis of several autoimmune and inflammatory diseases, a drug-delivery system which targets phagocytic cells was studied. We had previously demonstrated that Dexamethasone, a potent glucocorticoid analogue, can be encapsulated in erythrocytes and selectively delivered to macrophages (Magnani et al., Drug Delivery, 2151-155, 1995. In addition, lipopolysaccharide (LPS) stimulation of Dexamethasone-targeted macrophages results in the suppression of TNF-a secretion (D'Ascenzo et al., Erythrocytes us Drug Carrier in Medicine, [81][82][83][84][85][86][87][88] 1997). Here we demonstrate that Dexamethasone administration to macrophages by means of opsonized RBC allow to efficiently interfere with NF-kB activation. This NF-kB repression was in part mediated by induction of IkBa gene transcription and, as a consequence, by an increased rate of IkBa protein synthesis. Addition of LPS to macrophages targeted with Dexamethasoneloaded RBC resulted in a significant residual amount of IkBa and in a 40% inhibition of the NF-kB DNA binding activity. Furthermore, NF-kB inactivation correlated with down-modulation of TNF-a mRNA expression, demonstrating that suppression of TNF-a production in Dexamethasone targeted cells occurs at the transcriptional level. Although the same molecular mechanisms are involved in the immunosuppressive activity of free or RBC-loaded Dexamethasone, this second system of drug delivery offers the advantage of being extremely selective for cells of the monocyte/macrophage lineage.