Enfuvirtide

In: Drug

8 Jun 2010

EnfuvirtideAcquired immunodeficiency syndrome (AIDS) continues to pose an overwhelming burden on public health. According to estimates from the Joint United Nations Programme on HIV.

AIDS (UNAIDS) and the World Health

Organization (WHO), 38.6 million adults and 3.2 million children throughout the word were living with human immunodeficiency virus (HIV) infection at the end of 2002. This number is more than 50% higher than the figures projected by WHO in 1991, based on the available data at that time. The Centers for Disease Control and Prevention (CDC) estimates that 850,000 to 950,000 U.S. residents are infected with HIV, with 25% unaware of their current disease state. In 2002, five million people were infected with HIV and a total of 3.1 million people died of HIV/AIDS. Despite the advent of anti-retroviral therapy, this number is the highest throughout the world in any year since the beginning of the epidemic.Ā canadian discount pharmacy

The pathogenesis of HIV type 1 (HIV-1) has been published extensively. Thus, the knowledge gained paved the way for the development of new antiretroviral agents that are highly active against this strain. Resistance to most of the currently available antiretroviral drugs, however, is common. Although the combinations of these highly active antiretroviral drugs delay the emergence of viral resistance more effectively than monotherapy does, there are no known combinations that can guarantee the prevention of resistance development.

On March 13, 2003, the U.S Food and Drug Administration (FDA) approved a novel drug, the first in its class for the treatment of resistant HIV-1 infection. Enfuvirtide (FuzeonĀ®, Roche, Trimeris) represents a new class of antiretroviral agents known as fusion inhibitors. The FDA granted accelerated approval of this drug on the basis of two large clinical trials involving HIV patients who had not responded to conventional antiretroviral therapy.

PHARMACOLOGY

Enfuvirtide is a 36-amino acid peptide chain with 14 different amino acids. Linear in nature, its molecule is composed of naturally occurring L-amino acid residues; the N-terminus is acetylated, and the C-terminus is a carboxamide.

Unlike the existing antiretroviral drugs, enfuvirtide has a unique mechanism of action that is designed to block HIV fusion with the human immune cell. The virus is composed of two layers of fatty lipids that consist predominantly of proteins taken from the host cell upon budding and release. HIV also consists of its own surface proteins, called Env. This protein has a strong affinity for the CD4 receptor cell at which binding of the viron particle takes place.

HIV consists of appendages known as glycoprotein 120 and glycoprotein 41 (gp120 and gp41), which aid in viral attachment. gp120 is the capsule that anchors the virus, and gp41 is the domain of gp120 that holds the virus to the CD4 cell. HIV fusion with CD4 cells is accomplished through a series of con-formational changes in the HIV envelope as well as in gp120 and gp41. The core structure of glycoprotein 41 is a six-helix bundle composed of a 3N terminal and a 3C terminal helix. The C-helices closely surround the N-helices, and conforma-tional changes, which are manifested by folding into a hairpin shape, occur after binding to the target cell membrane.

Figure 1 Structure of the human immunodeficiency virus

Figure 1 Structure of the human immunodeficiency virus. (Adapted from UNAIDS Joint United Nations Programme on HIV/AIDS.

The pharmacological structure of enfu-virtide corresponds to the C-helix structure of gp41. Enfuvirtide binds to and inhibits the gp41 protein’s active site and thus disrupts the structural rearrangement that is necessary for the virus to gain entry into a healthy immune cell (Figure 1). Given this unique mechanism of action, enfuvirtide has the potential to act synergistically with the currently available antiretroviral drugs to suppress HIV-1 replication and to diminish the development of resistant mutations.
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