Human immunodeficiency virus reverse inhibitor

Rittinger K, Divita G, Goody R. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 1995 92 8046-8049. 

A potent specific telomerase inhibitor designated as telomestatin, 363, was isolated from Streptomyces anulatus 3533-SV4 <2001JA1262>. Although telomerase consists of several components with DNA polymerase or reverse transcriptase activity in addition to its intrinsic telomerase component, telomestatin specifically inhibited telomerase without affecting DNA polymerase and human immunodeficiency virus-reverse transcriptase (HIV-RT). 

Fig. 5.7. Activation, incorporation, and chain-terminating action of azidothymidine (AZT), a thymidine analogue, as a reversible inhibitor of human immunodeficiency virus-reverse transcriptase (HIV-RT).

Nakashima, H. Kudo, Y. Kobyashi, N. Motoki, Y. Neushul, M. Yamamoto, N. Purification and Characterization of an Avian Myeloblastosis and Human Immunodeficiency Virus Reverse Transcriptase Inhibitors, Sulfated Polysaccharides Extracted from Sea Mgdit Antimicrob. Agents Chemother. 1987, 31, 1524-1528. 

Lee WA, He GX, Eisenberg E, CUilar T, Swaminathan S, Mulato A, Cundy KC (2(X)5) Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemothta 49 1898—1906... 

Nakashima H, Kido Y, Kobayashi N, Motoki Y, Neushul M, Yamamoto N (1987) Purifications and characterization of an avian myoblastosis and human immunodeficiency virus reverse transcriptase inhibitor sulfated polysaccharides extracted from sea algae. Antimicrob Agents Chemoth 31 1524-1528... 

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

De Clercq E (1993) HlV-l-spedfic RT inhibitors highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med Res Rev 13 229-258... 

Gibson W (1996) Structure and assembly of the virion. Intervirology 39 389 00 Goldman ME, Nunberg JH, O Brien JA, Quintero JC, Schleif WA, Freund KF, Gaul SL, Saari WS, Wai IS, Hoffman JM et al. (1991) Pyridinone derivatives specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc Natl Acad Sci USA... 

Burke DH, Scales L, Andrews K, Gold L (1996) Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HlV-1) reverse transcriptase. J Mol Biol 264 650-666 Burrer R, Neuman BW, Ting JP, Stein DA, Moulton HM, Iversen PL, Kuhn P, Buchmeier MJ (2007) Antiviral effects of antisense morphoUno oligomers in murine coronavirus infection models, J Virol 81 5637-5648... 

Hertogs K, de Bethune MP, Miller V, Ivens T, Schel P, Van Cauwenberge A, Van Den Eynde C, Van Gerwen V, Azijn H, Van Houtte M, Peelers F, Staszewski S, Conant M, Bloor S, Kemp S, Larder B, Pauwels R (1998) A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother 42 269-276... 

Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

Najera I, Richman DD, Olivares I, Rojas JM, Peinado MA, Perucho M, Najera R, Lopez GaHndez C (1994) Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses 10 1479-1488 Nijhuis M, Boucher CAB, Schipper R Leitner T, Schuurman R, Albert J (1998) Stochastic processes strongly influence HIV-1 evolution during suboptimal protease inhibitor therapy. Proc Natl Acad Sci USA 95 14441-14446... 

Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ, Letendre S, Videen JS, McCutchan JA, Patterson TL, Grant I (2005) Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV-I-) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol ll(4) 356-364... 

Human immunodeficiency virus (HIV) is a retrovirus, i.e. its RNA is converted in human cells by the en me reverse transcriptase to DNA which is incorporated into the human genome and is responsible for producing new HIV particles. Zidovudine (azidothymidine, AZT Fig. 5.22F) is a stmctural analogue of thymidine (Fig. 5.22A) and is used to treat AIDS patients. Zidovudine is converted in both infected and uninfected cells to the mono-, di- and eventually triphosphate derivatives. Zidovudine triphosphate, the aetive form, is a potent inhibitor of HIV replication, being mistaken for thymidine by reverse transeriptase. Premature ehain termination of viral DNA ensues. However, AZT is relatively toxic because, as pointed out above, it is converted to the triphosphate by eellular enzymes and is thus also aetivated in uninfected cells. 

Isoniazid Daily for 9 monthsc,d In human immunodeficiency virus (HlV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). A (II) A (II)... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) A noncompetitive inhibitor of the viral reverse transcriptase enzyme that binds to the active site of the enzyme itself, rather than by terminating the enzymatic product. NNRTIs are only active against human immunodeficiency virus-1. 

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3 -thiacytidinc inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA 1993 90 5653-5656. 

Balzarini J, Perez-Perez M-J, San-Felix A, Schols D, Perno C-F, Vandamme A-M, Camarasa M-J, De Clercq E. 2, 5 -Bis-0-(tert-Butyldimethylsilyl)-3 -spiro- 5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)pyrimidine (TSAO) nucleoside analogues highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc Natl Acad Sci USA 1992 89 4392-4396. 

Nunberg JH, Schleif WA, Boots EJ, O Brien JA, Quintero JC, Hoffman JM, Emini EA, Goldman ME. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol 1991 ... 

Richman D, Shih C-K, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 1991 88 11241-11245. 

Mellors JW, Dutschman GE, Im G-J, Tramontano E, Winkler SR, Cheng Y-C. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 1992 41 446-451. 

Byrnes VW, Sardana W, Schleif WA, Condra JH, Waterbury JA, Wolfgang JA, Long WJ, Schneider CL, Schlabach AJ, Wolanski BS, Graham DJ, Gotlib L, Rhodes A, Titus DL, Roth E, Blahy OM, Quintero JC, Staszewski S, Emini EA. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1993 37 1576-1579. 

Thiourea compounds have been observed to inhibit human immunodeficiency virus (HIV) reverse transcriptase, a viral enzyme that is responsible for the reverse transcription of the retroviral RNA to proviral DNA. Phenethylthiazoylthiourea (PETT) compounds were discovered as potent inhibitors of HIV type 1 and display certain structure-activity relationships among various substituents in their structure.199 207 Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds.208 215... 

Up to this point, GIPF expressions have been formulated for only one type of biological activity - the inhibition of reverse transcriptase (RT), the enzyme that promotes the reverse transcription of genomic RNA into double-stranded DNA, a key step in the replication of the human immunodeficiency virus, HIV [82, 87]. Analytical representations were obtained for the anti-HIV potencies of three families of RT inhibitors the correlation coefficients are between 0.930 and 0.952. We are currently investigating the effects of applying the GIPF approach to certain portions of the molecules rather than their entireties. This might reveal the source of the activity, or alternatively, indicate it to be delocalized. 

Drugs are also used to inhibit the enzymatic reactions of foreign pathogens that enter the human body. An example is the use of reverse transcriptase inhibitor and protease inhibitor for combating the human immunodeficiency virus (HIV), as shown in Exhibit 2.12. Some new inhibitors are used to block HIV from attaching to the human cell, CD4, thus stopping replication and infection of other cells, as presented in Exhibit 2.13. 

The rapid spread of acquired immune deficiency syndrome (AIDS) has prompted numerous efforts to develop therapeutic agents against the human immunodeficiency virus type 1 (HIV-1) [2351. Efforts have focused on inhibition of the virally encoded reverse transcriptase (RT) enzyme, which is responsible for the conversion of retroviral RNA to proviral DNA. The nucleoside RT inhibitors 3 -azidothymidine (AZT) and dideoxyinosine (ddl) have proven to be clinically useful anti HIV-1 agents [236], but due to their lack of selectivity versus other DNA polymerases, these compounds are flawed by their inherent toxi-... 

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). 

An efficient synthesis of the l-aUyl-6-(l, 2, 3 -triazolyl) analogue 170 of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (KEPT), an anti-human immunodeficiency virus (HIV) reverse transcriptase inhibitor, was reported using an intermolecular 1,3-dipolar cycloaddition of the azide 169 with acetylenes (35) (Scheme 9.35). Azidouracil (169), when refluxed with an acetylene in equimolar proportions in toluene, gave the corresponding triazoles (170) in excellent yield. 

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