Structure-based design of AIDS drugs and the development of resistance

AIDS is a major worldwide epidemic spread primarily through contact with infected blood during sexual activity, drug injection, birth, and, rarely now, blood transfusion. More than a dozen drugs for the treatment of AIDS have been introduced in the last 15 years and the process leading to their development offers an excellent example of the progress made in the field of rational drug design. The principal targets of the approved drugs are reverse transcriptase and protease enzymes encoded by the human immunodeficiency virus. In particular, introduction of protease inhibitors has led to a significant decrease of the mortality and morbidity associated with AIDS. My presentation will discuss methods utilized for the development of selected AIDS drugs, primarily protease inhibitors, and the emergence of drug resistance which is presently the greatest challenge in fighting this disease in developed countries. In the last 15 years, introduction of over a dozen drugs against acquired immunodeficiency syndrome (AIDS) attests to the success of structure-assisted (rational) drug design and discovery. This approach utilizes techniques such as protein crystallography, nuclear magnetic resonance (NMR), and computational biochemistry to guide the creation and synthesis of potential drugs (1, 2). The complementary methods of computer-aided molecular design (3) and combinatorial chemistry (4) are now routinely employed in both the lead identification and the development phases of drug design. AIDS is caused by two variants of the human immunodeficiency virus, HIV-1 and HIV-2. The genomes of these retroviruses consist of three open reading frames (ORF), gag, pol, and env and encode only three enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR). All of these enzymes have become targets for drug discovery, although they are certainly not the only possible retroviral targets. The first AIDS drugs to be identified were nucleoside inhibitors of RT, discovered and developed long before the structure of RT itself (Fig. 1) was solved (5, 6). These analogs of the polynucleotide substrates bind in the substrate-binding site and can inhibit both HIV-1 and HIV-2 RT. The inhibitory properties of nucleoside analogs against RT are due either to the lack of 2' or 3' hydroxyl groups, or to their replacement by other functional groups. So far, one nucleotide and six nucleoside analogs (NRTIs) have been approved by the U.S. Food and Drug Administration (FDA). Zidovudine (azidothymidine, AZT, Retrovir) was approved for monotherapy in 1987 as the first generally available AIDS drug, although its efficacy in that mode was shown to be only transitory (7). Another nucleoside analog AIDS drug is didanosine (dideoxyinosine, ddl, Videx), an analog of inosine, lacking both the 2'- and 3'-hydroxyl groups on its ribose moiety. Other drugs in this category are zalcitabine (dideoxycytidine; ddC, Hivid), stavudine (d4T, 3'-deoxy-2'-thymidinene, Zerit), lamivudine (3TC, 3'-thia-2', 3'-dideoxcytidine, Epivir), and abacavir (Ziagen). Several combinations of these drugs have also been introduced. The most recently introduced drug is tenofovir (Viread), an analog of a nucleotide rather than a nucleoside. A completely distinct class of RT-directed drugs includes compounds called non-nucleoside inhibitors (NNI's).