Maturation Inhibitors | Fusion Inhibitors

The most urgent need in HIV therapy today is for new treatments that are effective against strains of the virus that are resistant to currently approved drugs including reverse transcriptase and protease inhibitors.  Our approach is to develop drugs that have activity against these resistant isolates because they act at different targets in the HIV life cycle.  Panacos’ proprietary discovery technologies focus on small molecule, orally available drugs against novel targets, including two critical steps in the HIV lifecycle, virus maturation and virus fusion.

Panacos scientists identified a new target for antiviral intervention:Virus Maturation, a process that occurs at the last stage in virus replication when virus is released from infected cells.

Panacos' lead HIV inhibitor, bevirimat (PA-457) , acts at this point in the virus life cycle and is the first in a new class of HIV drugs called Maturation Inhibitors. Bevirimat blocks HIV maturation by inhibiting the final step in the processing of the HIV Gag protein. The resulting virus particles are structurally defective and are incapable of spreading infection around the body. The mechanism of action of bevirimat is described in a November 2003 publication in the journal Proceedings of the National Academy of Sciences of the USA  (Li et al., Proc. Natl. Acad. Sci. USA, 100, 13555-13560 [2003]).

For further information on bevirimat's clinical development status, please click here .

Fusion Inhibitors

The first step in virus infection is fusion to a human cell, a key process that allows the virus to enter the cell. Once inside, the virus takes over the cell’s genetic machinery and generates new copies of itself that spread around the body causing disease. The viral proteins that mediate the fusion process represent novel targets for anti-HIV drug development. Our scientists are leaders in the discovery of viral fusion inhibitors and have developed proprietary technologies designed for the discovery of orally available small molecule fusion inhibitors. Such drugs could be administered as tablets or capsules and should have much greater market acceptance than protein-based therapeutics that must be injected and are expensive to manufacture.

The initial steps in HIV replication are mediated by the virus’ gp120 and gp41 surface proteins, which are functionally linked.  The gp120 molecule is involved in cell targeting and binds to CD4 and chemokine receptors.  These binding interactions drive a cascade of conformational changes in gp120 and gp41. The hydrophobic tip of gp41 penetrates the human cell membrane and ongoing conformational changes in gp41 then pull the HIV and human cell membranes together to initiate fusion.

Panacos focuses on discovering compounds that block the conformational changes in gp120/gp41 that drive the fusion event.  Our scientists have developed a patent-protected fusion inhibitor screening technology to discover HIV fusion inhibitors that operate by this mechanism.  They have successfully utilized this technology to identify several families of small molecule HIV fusion inhibitors. The Company is currently engaged in a program of medicinal chemistry to optimize these compounds and identify the first small molecule HIV fusion inhibitor suitable for IND filing