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The Appealing Story of HIV Entry Inhibitors

From Discovery of Biological Mechanisms to Drug Development

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Abstract

Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects, such as mitochondrial toxicity and lipodystrophy, and resistance, not only to individual drugs but to entire drug classes.

Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Two different HIV molecules have been selected as targets of drug inhibition so far: reverse transcriptase and protease. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a ‘new entry’ into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses.

There are several compounds that are at different developmental stages in the pipeline to counter HIV entry, among them: (i) the attachment inhibitor dextrin-2-sulfate; (ii) the inhibitors of the glycoprotein (gp) 120/CD4 interaction PRO 542, TNX 355 and BMS 488043; (iii) the co-receptor inhibitors subdivided in those targeting CCR5 (SCH 417690 [SCHD], UK 427857 GW 873140, PRO 140, TAK 220, AMD 887) and those targeting CXCR4 (AMD 070, KRH 2731); and (iv) the fusion inhibitors enfuvirtide (T-20) and tifuvirtide (T-1249).

The story of the first of these drugs, enfuvirtide, which has successfully completed phase III clinical trials, has been approved by the US FDA and by the European Medicines Agency, and is now commercially available worldwide, is an example of how the knowledge of basic molecular mechanisms can rapidly translate into the development of clinically effective molecules.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

Unrestricted Educational Grants from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Roche, Schering-Plough, Tibotec support the continuing clinical trials that take place at the Clinic of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. We are greatly indebted to the patient volunteers who take part in the trials.

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  1. Clinic of Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d’ Ancona 20, 20127, Milan, Italy

    Antonella Castagna, Priscilla Biswas, Alberto Beretta &  Adriano Lazzarin

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  1. Antonella Castagna
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  2. Priscilla Biswas
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Correspondence to Adriano Lazzarin.

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Castagna, A., Biswas, P., Beretta, A. et al. The Appealing Story of HIV Entry Inhibitors. CNS Drugs 65, 879–904 (2005). https://doi.org/10.2165/00003495-200565070-00001

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