Human immunodeficiency virus drugs targeting

FIGURE 84-1. Life cycle of HIV and targets for antiretroviral drugs. (From Fletcher CV, Kakuda TN. Human immunodeficiency virus infection. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 2258, with permission.)... 

Peptidases encoded by many viruses play essential roles at various stages of viral replication, including the coordinated assembly and maturation of virons [7a]. Viral peptidases have become important drug targets in the treatment of viral infections. Of note are inhibitors of proteases of the human immunodeficiency virus (HIV), particularly HIV-1 protease (HIV-1 retropepsin, EC 3.4.23.16) and HIV-2 protease [47-50], Drugs in this class, which include indinavir, ritonavir, and saquinavir, are useful in the treatment of AIDS, especially when administered as a cocktail together with one of the drugs that act on the viral retrotranscriptase (e.g., didanosine, stavudine, and zidovudine (AZT)). 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

The resolution of racemic FTC butyrate (34) was required for the synthesis of the antiviral drug emtricitabine (Emtriva) (Scheme 7.15) a nucleoside reverse transcriptase inhibitor targeted for treatment of human immunodeficiency virus (HIV) and hepatitis infections [35]. The racemic FTC butyrate ester (34) was treated with immobilized cholesterol esterase, which cleaved the required isomer to the corresponding alcohol (-) 35 with 91% and 52% conversion [36]. The product was isolated as the hydrochloride salt to give 31% yield (98% ) from the 8 kg demonstration. The esterase was immobilized by precipitation onto an accurel polypropylene support using acetone followed by cross linking with glutaralde-... 

Human immunodeficiency virus-1 (HIV-1) protease is an enzyme that breaks inactive polyproteins into their functional parts that are vital for the proper operation of HIV-1. This enzyme is a target for treatment of patients infected with HIV-1. HIV-1 protease operates as a dimeric complex, a trait that lends the enzyme to be inhibited by a drug that is highly symmetrical.24... 

The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease that has claimed the lives of tens of millions of people since the 1980s. Because of the vast impact of AIDS on global health, HIV and its molecular biology have been intensely studied to determine potential drug targets for intervention. 

Reverse transcription (which occurs in both prokaryotes and eukaryotes) is the synthesis of DNA from an RNA template. A class of RNA viruses, called retroviruses, are characterized by the presence of an RNA-dependent DNA polymerase (reverse transcriptase). The vims that causes AIDS, Human Immunodeficiency Virus (HIV), is a retro-vims. Because nuclear cell division doesn t use reverse transcriptase, the most effective anti-HIV drugs target reverse transcriptase, either its synthesis or its activity. Telomerase, discussed in the previous section, is a specialized reverse transcriptase enzyme. See Figure 12-5. 

What is the justification for direct public spending on targeted drug discovery In certain cases, public health authorities have determined that national priorities necessitate public investment to speed the process of developing new therapies. Illnesses related to human immunodeficiency virus (HIV) is one example. There may also be barriers to private-sector involvement. The orphan drug programs exist because some conditions affect so few patients that the private sector might otherwise find investment in potential treatments financially unprofitable. 

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