Enfuvirtide clinical development

Components of F-[IV entry and targets for entry inhibition including coreceptor blockers. There are many different stages of viral entry and each of these is specifically susceptible to antagonism by specific compounds. The compounds listed above are in clinical development with the exception of enfuvirtide, which was approved by the Food and Drug Administration (FDA). (Reprinted with permission from Dr. Robert W. Dorns. Available at http //cHnicaloptions.com. Accessed August 25, 2005.)... 

This chapter is intended to provide an overview of HIV-1 entry inhibitors, focusing on the mechanism of action, development, and knowledge of viral resistance to the currently available entry inhibitors, enfuvirtide and maraviroc. Although reversed relative to their order in the entry process, enfuvirtide is discussed first due to the greater clinical experience with this drug. 

One second-generation peptide, T-1249, was developed as a follow-on to enfuvirtide and progressed into phase II clinical studies (Lalezari et al. 2004, 2005b). The sequence of T-1249 was derived from HIV-1, HIV-2, and SIV HR-2 domains. 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

Cooper DA, Lange JMA (2004) Peptide inhibitors of virus-cell fusion enfuvirtide as a case study in clinical discovery and development. Lancet Infect Dis 4 426-436... 

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