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Notes: Summary This article focuses on the development of small synthetic inhibitors of cysteine proteases since 1990. The emphasis is on the design of selective cysteine protease inhibitors as research tools and as potential therapeutic agents. The mechanisms of inhibition of the new compounds, where appropriate, are discussed, and also how a knowledge of the differences in mechanisms between cysteine and serine proteases may be exploited in the design of selective inhibitors.

Notes: Abstract Almost two decades of unprecedented efforts in research costing US taxpayers over $50 billion have failed to defeat Acquired Immune Deficiency Syndrome (AIDS) and have failed to explain the chronology and epidemiology of AIDS in America and Europe. The failure to cure AIDS is so complete that the largest American AIDS foundation is even exploiting it for fundraising: ‘Latest AIDS statistics – 0,000,000 cured. Support a cure, support AMFAR.’ The scientific basis of all these unsuccessful efforts has been the hypothesis that AIDS is caused by a sexually transmitted virus, termed Human immunodeficiency virus (HIV), and that this viral immunodeficiency manifests in 30 previously known microbial and non-microbial AIDS diseases. In order to develop a hypothesis that explains AIDS we have considered ten relevant facts that American and European AIDS patients have, and do not have, in common: (1) AIDS is not contagious. For example, not even one health care worker has contracted AIDS from over 800,000 AIDS patients in America and Europe. (2) AIDS is highly non-random with regard to sex (86% male); sexual persuasion (over 60% homosexual); and age (85% are 25–49 years old). (3) From its beginning in 1980, the AIDS epidemic progressed non-exponentially, just like lifestyle diseases. (4) The epidemic is fragmented into distinct subepidemics with exclusive AIDS-defining diseases. For example, only homosexual males have Kaposi's sarcoma. (5) Patients do not have any one of 30 AIDS-defining diseases, nor even immunodeficiency, in common. For example, Kaposi's sarcoma, dementia, and weight loss may occur without immunodeficiency. Thus, there is no AIDS-specific disease. (6) AIDS patients have antibody against HIV in common only by definition–not by natural coincidence. AIDS-defining diseases of HIV-free patients are called by their old names. (7) Recreational drug use is a common denominator for over 95% of all American and European AIDS patients, including male homosexuals. (8) Lifetime prescriptions of inevitably toxic anti-HIV drugs, such as the DNA chain-terminator AZT, are another common denominator of AIDS patients. (9) HIV proves to be an ideal surrogate marker for recreational and anti-HIV drug use. Since the virus is very rare (〈 0.3%) in the US/European population and very hard to transmit sexually, only those who inject street drugs or have over 1,000 typically drug-mediated sexual contacts are likely to become positive. (10) The huge AIDS literature cannot offer even one statistically significant group of drug-free AIDS patients from America and Europe. In view of this, we propose that the long-term consumption of recreational drugs (such as cocaine, heroin, nitrite inhalants, and amphetamines) and prescriptions of DNA chain-terminating and other anti-HIV drugs, cause all AIDS diseases in America and Europe that exceed their long-established, national backgrounds, i.e. 〈95%. Chemically distinct drugs cause distinct AIDS-defining diseases; for example, nitrite inhalants cause Kaposi's sarcoma, cocaine causes weight loss, and AZT causes immunodeficiency, lymphoma, muscle atrophy, and dementia. The drug hypothesis predicts that AIDS: (1) is non-contagious; (2) is non-random, because 85% of AIDS causing drugs are used by males, particularly sexually active homosexuals between 25 and 49 years of age, and (3) would follow the drug epidemics chronologically. Indeed, AIDS has increased from negligible numbers in the early 1980s to about 80,000 annual cases in the early '90s and has since declined to about 50,000 cases (US figures). In the same period, recreational drug users have increased from negligible numbers to millions by the late 1980s, and have since decreased possibly twofold. However, AIDS has declined less because since 1987 increasing numbers of mostly healthy, HIV-positive people, currently about 200,000, use anti-HIV drugs that cause AIDS and other diseases. At least 64 scientific studies, government legislation, and non-scientific reports document that recreational drugs cause AIDS and other diseases. Likewise, the AIDS literature, the drug manufacturers, and non-scientific reports confirm that anti-HIV drugs cause AIDS and other diseases in humans and animals. In sum, the AIDS dilemma could be solved by banning anti-HIV drugs, and by pointing out that drugs cause AIDS – modeled on the successful anti-smoking campaign.