Problems and perspectives in the design of anti‐HIV‐1 agents

Abstract

The human immunodeficiency virus (HIV) that produces the acquired immune deficiency syndrome (AIDS) continues to evade all strategies for potential therapeutic intervention. Global efforts in the search for potential anti-HIV-I agents have mainly centered around the design of enzyme inhibitors and derivatives that inhibit viral binding or gene expression. Both nucleoside and non-nucleoside reverse transcriptase inhibitors have demonstrated potent anti-HIV-1 activity. However, toxicity considerations and the emergence of resistant strains will require further structural manipulations to diminish these undesirable properties. Protease inhibitors also exhibit activities at nanornolar concentrations, but many of these agents may suffer from problems of absorption and biodegradation. These apparent shortcomings have been circumvented by the preparation of peptidomimetic molecules. Similarly, smaller CD4 mirnetics have emerged as alternatives to the larger soluble CD4 derivatives as inhibitors of viral binding. Other viral binding inhibitors, the anionic molecules, suffer from an inherent inability to enter cells and potential anticoagulant activity. These properties may be remedied by rational analog design and synthesis. Oligonucleotides can be constructed to inhibit specific segments of selected regulatory genes of the virus. These agents have been critiqued on the basis of stability, cellular uptake, and assurance of hybridization. Once again, structure activity relationship studies have revealed that many of these apparent problems can be overcome. The more recently discovered agents belong to the unique classes of tat antagonists or viral uncoating inhibitors. o 1993 WiIey-Liss, Inc.

Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity

“…[1][2][3][4][5] The mechanism of action of AZT involves its conversion into the corresponding 5'-O-triphosphate, which inhibits the replication of the virus by competitive inhibition of the viral reverse transcriptase (RT) and by incorporation and subsequent chain termination of the growing viral DNA strand. [6] Despite the development of additional RT inhibitors and agents that block other crucial steps in viral infection and replication, AZT is still the most used anti-HIV agent. However, administration of AZT is frequently associated with a significant dose-dependent toxicity, particularly destruction of bone marrow cells, myopathy, and hepatic abnormalities.…”

Synthesis of Naphthalenesulfonic Acid Small Molecules as Selective Inhibitors of the DNA Polymerase and Ribonuclease H Activities of HIV-1 Reverse Transcriptase

“…In the DNA polymerase assay, the most active naphthalensulfonic acid compounds fall into two broad structural classes. Compounds 2, 4, and [16][17][18] the symmetrical class of derivatives consisting of either a flexible polymethylene spacer or an aromatic spacer, while compounds 1, 6, 23, 24, 26, and 27 are nonsymmetrical derivatives having lipophilic palmitoyl or cholesteryl moieties. We have previously reported that compound 1 possesses potent inhibitory activities towards recombinant HIV-1 and HIV-2 RT, which was superior to the known RT inhibitor, Suramin.7 On the basis of the above data, derivatives 6,16, 17, 23, 26, and 27 were chosen for determinations of 50% inhibitory concentration (IC50) values for the inhibition of RNA-dependent DNA polymerase activity (RDDP), DNA-dependent DNA polymerase activity (DDDP), and ribonuclease H (RNase H) activity of RT (Table 2).…”

Amino Acids in the Development of Prodrugs

“…Zidovudine (AZT, 3′-azido-3′-deoxythymidide, 19 , Figure 9 ) was the first 2′-3′-dideoxy-nucleoside (ddN) approved by US Food and Drug Administration (FDA) for treatment of patients suffering from AIDS [ 53 , 54 ]. The mechanism of action of 19 involves its conversion into the corresponding 5′- O -triphosphate, which inhibits the replication of the virus by competitive inhibition of the viral reverse transcriptase (RT) and by incorporation and subsequent chain termination of the growing viral strand [ 55 ]. Administration of 19 is frequently associated with a significant dose-dependent toxicity, additionally to its short half-time in human plasma which requires frequent administration to maintain therapeutic drug concentrations [ 56 , 57 ].…”