Fusion inhibitor

Enfuvirtide is a peptide that binds to the viral fusion protein in such a manner as to prevent the necessary change in conformation. It is a reserve drug. 

All rights reserved. Usage subject to terms and conditions of license. 

---

In this chapter, we have described the spectrum of antiviral activities that have been discovered beyond the world of nucleoside analogues, protease and fusion inhibitors. The compounds and mechanisms described here may one day add significantly to the armamentarium of antiviral agents, not only against Herpes Simplex, Hepatitis B and Human Immunodeficiency Virus, but also against Hepatitis C and Human Cytomegalovirus. 

Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381 661-666 Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gpl20. J Virol 74 8358-8367... 

Greenberg ML, Cammack N (2004) Resistance to enfuvirtide, the first HIV fusion inhibitor. J Antimicrob Chemother 54 333-340... 

Lalezari JP, Henry K, O Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M (2003c) Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 348 2175-2185... 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

NRTI NNRTI Fusion inhibitors Co-receptor antagonists ... 

Two classes of entry inhibitors have been developed. The first entry inhibitor approved as HIV therapy was enfuvirtide, a fusion inhibitor. In contrast with aU other antiretrovirals, this drug must be administered subcutaneously and twice a day, which represent important disadvantages to the patient. It is very potent and generally reserved for heavily antiretroviral-experienced patients with virologic failure. Unfortunately enfuvirtide shows a low genetic barrier for resistance (Fig. 2) and should be administered in combination with at least one other active drug. 

Fusion Inhibitors Enfuvirtide (T20) Injectable, in 90 mg (1 mL) No dosage N/A Local injection site reaction Catabolism to... 

III. VIRUS-CELL FUSION INHIBITORS LECTINS, ALBUMINS, AND TRITERPENE DERIVATIVES... 

The clinical potential of the fusion inhibitors in the therapy and/or prophylaxis of HIV infections remains a subject for further study. Since these compounds directly interfere with syncytium formation, they should be able to block HIV infections generated by both free virus particles and HIV-infected cells. It is not known how readily the virus may become resistant to this class of compounds. For betulinic acid, it has been ascertained that some HIV-1 strains (e.g., NDK) may be resistant ab initio. 

HIV fusion inhibitors, 3 151-152 HIV neuramidase inhibitors, target structure-based database searches, 6 14... 

WARNING Rarely causes allergy never rechallenge Uses w/ antiretroviral agents for HIV-1 Infxn in Tx-experienced pts w/ evidence of viral replication despite ongoing antiretroviral therapy Action Viral fusion inhibitor Dose 90 mg... 

Jiang S, Zhao Q, and Debnath AK. Peptide and nonpeptide HIV fusion inhibitors. Curr Pharm Des 2002 8 563-580. 

Chemical Class Fusion inhibitor, HIV polypeptide, synthetic I Clinical Pharmacology ... 

Mechanism of Action A fusion inhibitor that interferes with the entry of HIV-1 into CD4-I- cells by inhibiting the fusion of viral and cellular membranes. Therapeutic Effect Impairs HIV replication, slowing the progression of HIV infection. Pharmacokinetics Comparable absorption when injected into subcutaneous tissue of abdomen, arm, or thigh. Protein binding 92%. Undergoes catabolism to amino acids. Half-life 3.8 hr. 

Fuzeon (enfuvirtide) Anti-AIDS (fusion inhibitor) 36 Chemical synthesis... 

In addition to fusion inhibitors, novel viral enzymes (e.g., integrase) are also being studied integrase inhibitors may constimte a new direction in antiviral therapy. Viral serine proteases have likewise been identified as attractive antiviral targets. Based upon crystallographic structural data, novel peptidomimetic inhibitors are being developed. 

Enfuvirtide Fusion inhibitor 90 mg subcutaneously bid Store at room temperature as a powder refrigerate once reconstituted Local injection site reactions, hypersensitivity reaction ... 

Enfuvirtide is a synthetic 36 -amino -acid peptide fusion inhibitor that blocks entry into the cell (Figure 49-4). Enfuvirtide, binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes. It has no activity against HIV-2. Enfuvirtide must be administered by subcutaneous injection. Metabolism appears to be by proteolytic hydrolysis without involvement of the CYP450 system. Elimination half-life is 3.8 hours. 

Resistance to maraviroc is associated with one or more mutations in the V3 loop of gpl20. There appears to be no cross-resistance with drugs from any other class, including the fusion inhibitor enfuvirtide. However, virologic failure of regimens containing maraviroc may potentially be caused not only by resistance but also by emergence... 

---