Design, Synthesis and Screening of Novel PCU-peptide/peptoid Derived HIV Protease Inhibitors (original) (raw)
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Antiretroviral Drugs Development; Past, Present and Future
Thirty years after the discovery of human immunodeficiency virus (HIV), more than 29 antiretroviral have been introduced. HIV at present can be managed though; it comes with consequences such as toxicity due to long term use of antiretroviral, development of resistance by HIV-1 strains and other viral or bacterial infections associated with it. Issues such as latency, socioeconomic problem in the developing world has been of considerable concern. The benefits of highly active antiretroviral therapy (HAART) in the developed countries far outweighed those in the underdeveloped nations. HIV belongs to the genus Lentivirus and family Retroviridae, possess a diploid RNA and a cone shaped capsid core particles. The virus consists of major and minor structural and nonstructural proteins that perform different roles in the virus life cycle. In this review we seek to give a comprehensive account of the past, present and future directions in the development of antiretroviral drug. There are five classes of antiretroviral inhibitors which target HIV-1's reverse transcriptase, protease, integrase, envelope fusion and co-receptor binding thereby disrupting virus replicative cycle. Strategies have emerged on how to better manage HIV Review Article
Human immunodeficiency virus protease inhibitors From drug design to clinical studies
Advanced Drug Delivery Reviews, 1997
The human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs)-saquinavir, ritonavir, nelfinavir, and indinavir-interact with the ABC-type multidrug transporter proteins MDR1 and MRP1 in CEM T-lymphocytic cell lines. Calcein fluorescence was significantly enhanced in MDR1 ؉ CEM/VBL100 and MRP1 ؉ CEM/VM-1-5 cells incubated in the presence of various HIV PIs and calcein acetoxymethyl ester. HIV PIs also enhanced the cytotoxic activity of doxorubicin, a known substrate for MDR1 and MRP1, in both VBL100 and VM-1-5 CEM lines. Saquinavir, ritonavir, and nelfinavir enhanced doxorubicin toxicity in CEM/VBL100 cells by approximately three-to sevenfold. Saquinavir and ritonavir also enhanced doxorubicin toxicity in CEM/VM-1-5 cells. HIV-1 replication was effectively inhibited by the various PIs in all of the cell lines, and the 90% inhibitory concentration for a given compound was comparable between the different cell types. Therefore, overexpression of MDR1 or MRP1 by T lymphocytes is not likely to limit the antiviral efficacy of HIV PI therapy.
Increasing number of anti-HIV drugs but no definite cure Review of anti-HIV drugs
Pharmacy World & Science, 2004
This review surveys the different classes of drugs. Method: We searched electronic databases and selected articles about pharmacotherapy with anti-retroviral drugs. Results: We discuss anti-retroviral drugs: the nucleotide reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the protease inhibitors (PIs). The combination of a PI and two NRTIs is very effective and lowers the viral load to below the limit of detection. However, it is not yet possible to eliminate the virus completely. Recently, the first member of a brand new class of drugs has become available, the fusion inhibitor enfuvirtide. We also discuss the problems associated with combining anti-retroviral drugs, such as compliance, resistance and serious side effects. Discussion. It is important to investigate new combinations with new classes of drugs, like the fusion inhibitors, for better effectiveness and fewer side effects.
Antimicrobial Agents and Chemotherapy, 2000
BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC 50 ) of 2.6 to 5.3 nM and an EC 90 of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500-to 23,000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects.