Presidio Pharmaceuticals, Inc.

Development Pipeline

Novel Nucleoside Reverse Transcriptase Inhibitor (NRTI)

PPI-801/802 (formerly MIV-410): Is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action. Unlike other NRTIs that are chain terminators (AZT, 3TC, ddI, d4T, abacavir etc.), PPI-801 inserts in the nascent cDNA chain at a penultimate position allowing one additional nucleoside to be incorporated but with a modified orientation. This mechanism of action prevents standard RT escape mutations such as Thymidine Analog Mutations (TAM) and Nucleoside Analog Mutations (NAM) from excising PPI-801 as they do with other NRTIs.

PPI-801 is effective at inhibiting a wide variety of NRTI resistant mutants and exhibits good safety profile in standard in vitro toxicity assays and in vivo animal studies including rodents and non-human primates.

PPI-801 is expected to be a once-a-day low dose therapy for individuals failing existing NRTIs as well as a potential first line therapy for newly infected individuals. We are advancing a promising prodrug of PPI-801 called PPI-802 through preclinical and IND-enabling studies over the next twelve months. This prodrug is more orally bioavailable than the parent molecule when tested in animal studies.

Programs

Nuclear Exclusion Technology (NEXT™):

Presidio's Nuclear Exclusion Technology (NEXT™) is a novel strategy that attacks HIV-1 before the pathogen can reproduce. After the virus infects human cells, the genetic material is converted to DNA with a protein called reverse transcriptase (RT). The next step in infection is the movement (importation) of the viral genes into the target cell's "nucleus," a compartment where the human chromosomes and genome are duplicated. By blocking this translocation of the HIV-1 genes into the nucleus with a specific compound, viral replication is inhibited. Presidio has licensed several novel compounds that reduce the replication of HIV genes under laboratory conditions. These compounds are small, are easily synthesized, have been shown to be non-toxic in small animals, and may be taken orally. The lead NEXT™ HIV-1 compound is currently in lead optimization.

Presidio has also initiated discovery and optimization of second-generation NEXT™ lead compounds specific for HIV-1 and other chronic viruses including HBV, HDV, HPV, CMV and Influenza.

PPI-367: Represents the first of a new class of small molecule NEXT™ inhibitors of HIV-1. PPI-367 was selected through structure-based design and molecular modeling of a 200,000 compound library using the resolved NMR and X-ray structures of the HIV-1 Matrix (MA) protein. Subsequent evaluation in cell-based HIV-1 infectivity assays revealed that PPI-367 was the most potent of the ~100 compounds selected from the modeling screen.

The mechanism of action of PPI-367 was verified using cell free and cell based biding studies and nuclear exclusion assays. PPI-367 is currently in lead optimization using medicinal chemistry and other drug enhancing methodologies and approaches.

HCV NS5A:

Replication of hepatitis C virus in the cytoplasm of target cells requires anchoring of the viral nucleoprotein complex (VNP) to intracellular membranes. This process was shown by Dr. Jeffrey Glenn (Stanford University), a member of Presidio’s CSAB, to be mediated primarily by two viral nonstructural proteins, NS5A and NS4B. Dr. Glenn elucidated this mechanism by identifying discreet domains within N-terminal amphipathic helices in the proteins that are required for the successful attachment and virus replication.

Presidio had licensed this technology from Stanford University and has initiated a program to identify new chemical entities (NCE) that mimic an inhibitory peptide shown by Dr. Glenn to interrupt the ability of NS5A to anchor the HCV VNP to cellular membranes. This peptide blocked the in-vitro replication of the VNP in an established replicon system. Presidio is conducting the work in collaboration with Dr. Glenn and Dr. Eddy Arnold (Rutgers University), who is also a member of Presidio’s CSAB.


	Development Pipeline Novel Nucleoside Reverse Transcriptase Inhibitor (NRTI) PPI-801/802 (formerly MIV-410): Is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action. Unlike other NRTIs that are chain terminators (AZT, 3TC, ddI, d4T, abacavir etc.), PPI-801 inserts in the nascent cDNA chain at a penultimate position allowing one additional nucleoside to be incorporated but with a modified orientation. This mechanism of action prevents standard RT escape mutations such as Thymidine Analog Mutations (TAM) and Nucleoside Analog Mutations (NAM) from excising PPI-801 as they do with other NRTIs. PPI-801 is effective at inhibiting a wide variety of NRTI resistant mutants and exhibits good safety profile in standard in vitro toxicity assays and in vivo animal studies including rodents and non-human primates. PPI-801 is expected to be a once-a-day low dose therapy for individuals failing existing NRTIs as well as a potential first line therapy for newly infected individuals. We are advancing a promising prodrug of PPI-801 called PPI-802 through preclinical and IND-enabling studies over the next twelve months. This prodrug is more orally bioavailable than the parent molecule when tested in animal studies. Programs *Nuclear Exclusion Technology (NEXT™):* Presidio's Nuclear Exclusion Technology (NEXT™) is a novel strategy that attacks HIV-1 before the pathogen can reproduce. After the virus infects human cells, the genetic material is converted to DNA with a protein called reverse transcriptase (RT). The next step in infection is the movement (importation) of the viral genes into the target cell's "nucleus," a compartment where the human chromosomes and genome are duplicated. By blocking this translocation of the HIV-1 genes into the nucleus with a specific compound, viral replication is inhibited. Presidio has licensed several novel compounds that reduce the replication of HIV genes under laboratory conditions. These compounds are small, are easily synthesized, have been shown to be non-toxic in small animals, and may be taken orally. The lead NEXT™ HIV-1 compound is currently in lead optimization. Presidio has also initiated discovery and optimization of second-generation NEXT™ lead compounds specific for HIV-1 and other chronic viruses including HBV, HDV, HPV, CMV and Influenza. PPI-367: Represents the first of a new class of small molecule NEXT™ inhibitors of HIV-1. PPI-367 was selected through structure-based design and molecular modeling of a 200,000 compound library using the resolved NMR and X-ray structures of the HIV-1 Matrix (MA) protein. Subsequent evaluation in cell-based HIV-1 infectivity assays revealed that PPI-367 was the most potent of the ~100 compounds selected from the modeling screen. The mechanism of action of PPI-367 was verified using cell free and cell based biding studies and nuclear exclusion assays. PPI-367 is currently in lead optimization using medicinal chemistry and other drug enhancing methodologies and approaches. *HCV NS5A:* Replication of hepatitis C virus in the cytoplasm of target cells requires anchoring of the viral nucleoprotein complex (VNP) to intracellular membranes. This process was shown by Dr. Jeffrey Glenn (Stanford University), a member of Presidio’s CSAB, to be mediated primarily by two viral nonstructural proteins, NS5A and NS4B. Dr. Glenn elucidated this mechanism by identifying discreet domains within N-terminal amphipathic helices in the proteins that are required for the successful attachment and virus replication. Presidio had licensed this technology from Stanford University and has initiated a program to identify new chemical entities (NCE) that mimic an inhibitory peptide shown by Dr. Glenn to interrupt the ability of NS5A to anchor the HCV VNP to cellular membranes. This peptide blocked the in-vitro replication of the VNP in an established replicon system. Presidio is conducting the work in collaboration with Dr. Glenn and Dr. Eddy Arnold (Rutgers University), who is also a member of Presidio’s CSAB.