RESUMEN
Determinations of only a very few protein structures had consequences comparable to the impact exerted by the structure of the protease encoded by HIV-1, published just over 25 years ago. The structure of this relatively small protein and its cousins from other retroviruses provided a clear target for a spectacularly successful structure-assisted drug design effort that offered new hope for controlling the then-escalating AIDS epidemic. This reminiscence is limited primarily to work conducted at the National Cancer Institute, and is not meant to be a comprehensive history of the field, but is rather an attempt to provide a very personal account of how the structures of this most thoroughly studied crystallographic target were determined.
Asunto(s)
Proteasa del VIH/historia , VIH-1/enzimología , Cristalografía por Rayos X , Descubrimiento de Drogas/historia , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/historia , Infecciones por VIH/virología , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/historia , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , VIH-1/fisiología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Modelos Moleculares , National Cancer Institute (U.S.)/historia , Estructura Cuaternaria de Proteína , Estados UnidosRESUMEN
HIV/AIDS not only represents the most severe epidemic in modern times, but also the greatest public health challenge in history. The response of the scientific community has been impressive and in just a few years, turned an inevitably fatal disease into a chronic manageable although not yet curable condition. The development of antiretroviral therapy is not only the history of scientific advancements: it is the result of the passionate 'alliance' towards a common goal between researchers, doctors and nurses, pharmaceutical industries, regulators, public health officials and the community of HIV-infected patients, which is rather unique in the history of medicine. In addition, the rapid and progressive development of antiretroviral therapy has not only proven to be life-saving for many millions but has been instrumental in unveiling the inequities in access to health between rich and poor countries of the world. Optimal benefits indeed, are not accessible to all people living with HIV, with challenges to coverage and sustainability in low and middle income countries. This paper will review the progress made, starting from the initial despairing times, till the current battle towards universal access to treatment and care for all people living with HIV.
Asunto(s)
Antirretrovirales/historia , Infecciones por VIH/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa/historia , Países Desarrollados , Países en Desarrollo , Didesoxinucleósidos/historia , Inhibidores de la Proteasa del VIH/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inhibidores de la Transcriptasa Inversa/historiaRESUMEN
Soon after its discovery, the attempts to develop anti-AIDS therapeutics focused on the retroviral protease (PR)-an enzyme used by lentiviruses to process the precursor polypeptide into mature viral proteins. An urgent need for the three-dimensional structure of PR to guide rational drug design prompted efforts to produce milligram quantities of this enzyme. However, only minute amounts of PR were present in the HIV-1 and HIV-2 viruses, and initial attempts to express this protein in bacteria were not successful. This review describes X-ray crystallographic studies of the retroviral proteases carried out at NCI-Frederick in the late 1980s and early 1990s and puts into perspective the crucial role that the total protein chemical synthesis played in unraveling the structure, mechanism of action, and inhibition of HIV-1 PR. Notably, the first fully correct structure of HIV-1 PR and the first cocrystal structure of its complex with an inhibitor (a substrate-derived, reduced isostere hexapeptide MVT-101) were determined using chemically synthesized protein. Most importantly, these sets of coordinates were made freely available to the research community and were used worldwide to solve X-ray structures of HIV-1 PR complexes with an array of inhibitors and set in motion a variety of theoretical studies. Publication of the structure of chemically synthesized HIV-1 PR complexed with MVT-101 preceded only by six years the approval of the first PR inhibitor as an anti-AIDS drug.
Asunto(s)
Proteasa del VIH/química , VIH-1/enzimología , VIH-2/enzimología , Cristalografía por Rayos X/historia , Proteasa del VIH/historia , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/historia , Historia del Siglo XX , Oligopéptidos/química , Oligopéptidos/historia , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
HIV protease plays a crucial role in the viral life cycle and is essential for the generation of mature infectious virus particles. Detailed knowledge of the structure of HIV protease and its substrate has led to the design of specific HIV protease inhibitors. Unfortunately, resistance to all protease inhibitors (PIs) has been observed and the genetic basis of resistance has been well documented over the past 15 years. The arrival of the early PIs was a pivotal moment in the development of antiretroviral therapy. They made possible the dual class triple combination therapy that became known as HAART. However, the clinical utility of the first generation of PIs was limited by low bioavailability and high pill burdens, which ultimately reduced adherence and limited long-term viral inhibition. When therapy failure occurred multiple protease resistance mutations were observed, often resulting in broad class resistance. To combat PI-resistance development, second-generation approaches have been developed. The first advance was to increase the level of existing PIs in the plasma by boosting with ritonavir. The second was to develop novel PIs with high potency against the known PI-resistant HIV protease variants. Both approaches increased the number of protease mutations required for clinical resistance, thereby raising the genetic barrier. This review provides an overview of the history of protease inhibitor therapy, its current status and future perspectives. It forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH/efectos de los fármacos , Farmacorresistencia Viral , Inhibidores de la Proteasa del VIH/historia , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Viracept (nelfinavir) is an HIV protease inhibitor supplied by Roche outside the US, Canada and Japan. Viracept was first introduced by Roche in 1998. Although newer protease inhibitors have become available for the treatment of HIV, it is viewed as a useful medicine for patients who are intolerant to ritonavir (since it does not require ritonavir boosting), pregnant women, and patients in resource-limited settings, since the formulation is heat-stable and does not require refrigeration. The relatively high prevalence of HIV in some of the third world countries means that it was also a product of choice for young women of childbearing age, pregnant and nursing women and young children. On 18 May 2007 F. Hoffmann-La Roche received first reports of a "bad smell" of blisterpacked Viracept tablets and one adverse drug report of nausea and vomiting from patients in Spain. Subsequently, ethyl methanesulfonate (EMS), an established mutagen, carcinogen and teratogen was identified as the potential source of the bad smell. On 6 June 2007, Viracept was globally recalled as the extent of the contamination exceeded the guidances for permissible levels set by regulatory authorities by more than 1000-fold and hence human risk was not readily assessable. In the following, a compilation of the course of events from a non-clinical point of view is presented. This compilation only partially reflects the complexity of the case and the interactions between all parties between May/June 2007 and September 2008 and hence necessarily remains partly a subjective compilation of the authors of this article. This compilation serves also as an introduction into this Special Issue of Toxicology Letters. The data on the cause and levels of contamination, likely duration of intake and affected patient population can be found in the subsequent contributions. Most importantly, we share in other parts of this Special Issue with the scientific community the data and risk assessment arguments that supported the conclusion by the company and regulatory authorities that the levels of contamination with EMS posed no health risk to affected patients.