Download Microbiotix has developed a pipeline of novel anti

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VIROLOGY RESEARCH:
Virus infection is a dynamic process involving a myriad of cellular and viral proteins. It starts
with the attachment of the virus to the host cell and finishing with the release of the progeny
virions from the cell. Microbiotix has two main targets for anti-viral drug discovery: (1). key viral
enzymes polymerases and proteases that are required for the replication of viruses in host cells
and (2) the viral entry process. Our pipeline includes programs for the treatment of human
cytomegalovirus infection, respiratory syncytial virus, hepatitis C, and avian Influenza H5N1.
Targeting of viral polymerase.
Targeting the viral entry
The first step, of a productive viral infection requires the binding of viral envelope proteins to
specific cell surface receptors. This selective association between viral envelope proteins is a
multistep process and requires highly specific sequential engagements between the viral
envelope proteins and specific cell surface receptors and/or, coreceptors. Blocking viral entry
into its target cell leads to suppression of viral infectivity, replication, and the cytotoxicity induced
by virus-cell interaction.
Respiratory Syncytial Virus (RSV) infections is the primary cause of hospitalisation in the first
year of life for children in most parts of the world, and nearly 100% of children in the USA are
infected with the virus by 2 to 3 years of age. The two viral envelope proteins include the fusion
(F) protein and the attachment (G) protein which are essential for viral penetration and
attachment to the host cells. Microbiotix has developed MBX300, sulfated sialyl lipid that
inhibits RSV infection in vitro and in animal models. MBX300 acts on the G protein and inhibits
the binding of virus to the cell membrane. MBX300 has also shown good activity against other
RNA virus including hepatitis C virus in vitro. Therefore, the possibility exists that MBX300 may
have broader activity and advantages against multiple viral pathogens. We are exploring the
activity against other viruses. Microbiotix is planning to start IND enabling preclinical toxicology
and safety pharmacology studies for MBX 300.
Hepatitis C Virus (HCV) is recognized as a worldwide health problem affecting over 170 million
people. HCV causes a spectrum of disease ranging from an asymptomatic carrier state to endstage liver disease; which includes cirrhosis and hepatocellular carcinoma. A vaccine for HCV is
currently not available. The present therapies for HCV infection rarely result in viral clearance,
are difficult to administer and cause serious toxic side effects. There are several drugs that have
been developed and under trial for HCV infection. These drugs are targeting the HCV-encoded
serine protease (NS3) and RNA polymerase (NS5B) that have emerged as a favourite target in
the race for new anti-HCV drugs. Microbiotix has an active program to develop entry inhibitors
against the HCV. However, unlike others we are targeting the viral entry process by attacking
the selective interaction between viral envelope glycoproteins and specific cell-surface
receptor(s). Since this virus is difficult to culture in vitro we have generated pseudotype virus
expressing HCV envelope glycoproteins as surrogate model to screen for inhibitors that target
the viral entry process. HCV, like HIV has a high mutation rate and therefore there will be high
probability for the emergence of drug-resistant virus. Combination therapy, either with the
existing treatments or with other specific antiviral drugs, will be needed to control the virus — a
point that underscores the importance of continuing to develop inhibitors against various viral
targets. Therefore the development of this entirely new class of inhibitors will have enormous
impact on the treatment and management of chronic HCV infection. Furthermore, the FDA
approval of the HIV fusion inhibitor T20 (enfuvirtide/Fuzeon) demonstrates the clinical
feasibility of this anti-viral approach
Recent outbreaks of highly pathogenic avian influenza A (H5N1) infections in poultry and in
humans (through direct contact with infected birds), have highlighted the need to develop new
anti-influenza therapeutics that will be active against all subtypes, including a newly emerged
pandemic strain. Vaccines, the main strategy for protection against influenza epidemics, will not
be effective against emerging strains not present in the vaccine. The currently available, antiinfluenza drugs, viral M2 ion-channel inhibitors (amantadine and its derivative) and
neuraminidase (NA) inhibitors (oseltamivir and zanamivir) have limited success because of their
strain specificity and emergence of drug resistance strains. We are developing new antiinfluenza therapeutics; that is targted against the highly conserved fusion and receptor binding
domain of the envelope protein hemagglutinin (HA). A novel inhibitor targeting either of the
conserved sites should be active against multiple subtypes, including a newly emerged
pandemic strain. For drug discovery, we have generated a pseudotype virus expressing HA
from pandemic H5N1 strain, as a surrogate model, to mimic HA mediated entry. This surrogate
model system is being used to screen for inhibitors against HA of pathogenic avian influenza A
(H5N1) virus under BSL2 conditions.
BATERIOLOGY RESEARCH:
Novel Antibiotic Targeting Bacterial DNA Polymerases
The objective of this project is to develop novel antibiotic to treat antibiotic-resistant grampositive (Gr+) and gram-negative (Gr-) bacterial infections. The work utilizes the class III
bacterial DNA polymerase (pol III), an unexploited target. The bacterial pol IIIs are highly
conserved enzymes that are required for the synthesis of DNA during chromosomal replication.
When an inhibitor of pol III is applied to a growing bacterium, it stops replication, and, thus, like
the replication-specific quinolone antibiotics, it is bactericidal. Furthermore, the pol III-selective
inhibitors are equally effective against clinically relevant antibiotic-resistant and antibioticsensitive pathogens. Using our proprietary antibiotic discovery platforms (Bacto-III and Replix) ,
we have developed a novel class of inhibitors active against DNA polymerase (pol) IIIC and E.
The new family of compounds have displayed favorable properties (i.e. inhibition of Gr+ DNA
polymerases as well as bacteria, low in vitro mammalian toxicity) and we are optimizing the
most promising structure utilizing a rational drug design approach to develop antibacterial lead
compounds
Bacterial DNA Helicases: Targets for Novel Antibiotics
We are developing new chemical classes of anti-bacterials that will target replicative DNA
helicase (RDH), an essential target in the DNA replication pathway and use them to treat
resistant organisms. For this purpose, we have developed a high throughput screen to identify
inhibitors of the Staphylococcus aureus RDH, that will detect inhibitors of any of the multiple
essential helicase functions, including strand unwinding, ATPase-coupled translocation, DNA
binding, and protein-protein interactions.
Novel Therapies for Staphylococcal BioFilm-Related Infections
Biofilms are surface attached bacterial communities encased in a hydrated matrix of
exopolysaccharide. In the body, infecting bacteria form biofilms on medical implants, such as
indwelling catheters. In this biofilm mode of growth, they are resistant to antibiotics and attack
by the body's immune system. Staphylococcal biofilms are the leading cause of hospital
acquired implant-based infections, which result in approximately 30,000 deaths per year. S.
epidermidis is the leading cause of these infections. The overall goal of this project is to
discover drugs that selectively block the formation of staphylococcal biofilms. These drugs will
be used to coat the surfaces of medical implants to prevent biofilm development when implants
are placed in patients.
Type III Secretion Inhibitors for Anti-Infective Therapy
Pseudomonas aeruginosa is a common and extremely virulent cause of serious infections in
immune- compromised/suppressed patients (e.g., HIV and cancer), cystic fibrosis patients, and
those on mechanical ventilation or with burn wounds. Frequent antibiotic resistance and the
highly virulent nature of P. aeruginosa make it deadlier than most other bacteria. New chemical
classes of antibiotics acting on novel accessible targets are crucial for continued effective
therapy against P. aeruginosa because such drugs will not be subject to existing resistance
mechanisms. The strategy of this project is to develop new drugs by screening a diverse
collection of synthetic and natural product compounds against extra-cellular targets that are
critical for virulence. The type III secretion system (TTSS), dedicated to the secretion of toxins
and their translocation into the cytoplasm of human cells has been validated as a clinically
important target in P. aeruginosa. The goal of this project is to identify specific inhibitors of
TTSS and to develop them into novel antibiotics for therapy against P. aeruginosa.
BIODEFENSE RESEARCH:
New anti-infectives based on novel chemical scaffolds are vital to the biodefense armory
primarily because they will be effective against both natural and engineered resistant forms of
bioterrorist microbes. Our research efforts are focused on the discovery and development of
novel therapeutic agents for the treatment of Ebola Virus infection, and against Bacillus
anthracis and Burkholderia pseudomalli
Development of Entry Inhibitors Against Ebola Virus Infection:
Ebola virus (EBOV) is an aggressive pathogen that causes highly lethal viral hemorrhagic fever
syndrome. EBOV is believed to be indigenous to Africa and causes periodic outbreaks of severe
viral hemorrhagic fevers in the continent, with a ~50-90% mortality rate in infected patients. It
has been classified as a Category A bioweapons agent by the Centers for Disease Control and
Prevention (CDC). Currently, there is no FDA approved vaccine or antiviral drug (not even an
experimental one) that is effective against EBOV infections in humans. The rapid progression of
EBOV infection also offers little opportunity to develop acquired immunity. Therefore, there is a
critical need for development of effective therapies to respond to post-exposure prophylaxis
during outbreaks of EBOV infection, and to counter potential acts of bioterrorism. We are trying
to block the entry step of the EBOV infection. We have generated pseudotype virus expressing
EBOV envelope glycoproteins as surrogate model to screen for inhibitors that target the viral
entry process in BSL2 laboratory. Microbiotix is utilizing two main platforms for developing entry
inhibitors against EBOV infection: 1. High-througput screening of library of small molecules to
discover unique anti-EBOV drug candidate and 2. structure-based drug design targeting the
cellular cysteine proteases Cathepsin B and Cathepsin L that are essential for EBOV infection.
Sensing Biowarfare Agents by Surface Enhanced Raman
The goal of this project is to develop a platform tool based on surface enhanced Raman
scattering (SERS) microscopy for the simultaneous rapid detection and identification of a broad
range of category A-C priority bacterial pathogens. The SERS microscopic diagnostic platform
will provide rapid, reagentless, specific identification of species within minutes, and will be
developed as a portable device for field use. We are developing a reference base for SERS
spectra. We are also in process of developing rapid, robust methods of enriching bacteria from
clinical samples for SERS and optimizing the SERS substrate performance.
Development of Screens for Bacillus anthracis Targets
The goal of this research is to discover and develop novel antibiotics effective against B.
anthracis, including resistant forms of this organism, for biodefense. Our strategy is to screen for
novel inhibitors against DNA polymerase III C (pol lII C) and topoisomerase IV (topo IV). Using
non-pathogenic B. anthracis Sterne strain, we have developed a permeable-cell DNA replication
pathway screen and is screening our library of small molecules to discover unique drug
candidates against B. anthracis infections.
Discovery of Burkholderia pseudomallei Therapeutics for Biodefense
B. pseudomallei is a bioterrorist threat. With the best current therapies, lethality is typically as
high as 40%. The overall goal of this application is the development of new drugs against this
organism. We are exploiting the high sequence similarity between B. pseudomallei and its less
virulent relative P. aeruginosa and is in process of develoing innovative screens for rapid, safe
discovery of effective therapeutic agents. The two species are similar in genome size and
composition, with nucleotide and amino acid sequence identities for many genes in the 50-70%
range, and in their mechanisms of drug resistance.