Dawson M.J.,Novacta Biosystems |
Scott R.W.,PolyMedix, Inc.
Current Opinion in Pharmacology | Year: 2012
Antimicrobial peptides from either microbial sources, or based on host defense peptides (HDPs) from higher organisms, show promising activity against human pathogens. Lantibiotics have been extensively engineered by either molecular biology approaches or chemistry and both natural and modified entities have been shown to have good efficacy in animal models of infection. Amongst HDPs either truncated peptides or non-peptide mimetic molecules show substantial promise both for their direct antibiotic action and also modulation of host functions. Members of both classes have reached clinical development for therapy of systemic infections and Clostridium difficile infection of the gastrointestinal tract. © 2012 Elsevier Ltd.
PolyMedix, Inc. | Date: 2012-10-23
The present invention provides methods of inhibiting the growth of Mycobacterium species or treating an animal having a Mycobacterium infection (including multi-drug resistance strains and extensively drug resistant strains) by administering a compound of the invention, a salt thereof, or a composition comprising the same.
PolyMedix, Inc. | Date: 2012-12-19
The present invention provides methods for preparing a polymeric compound of Formula I: or pharmaceutically acceptable salt thereof. The present invention also provides useful intermediates for preparing the compound of Formula I or pharmaceutically acceptable salt thereof.
PolyMedix, Inc. | Date: 2012-10-26
The present invention discloses ophthalmic and otic compositions of facially amphiphilic antimicrobial polymers and oligomers and their uses, including their use in methods for treating and preventing ophthalmic infections and otic infections in humans and animals.
PolyMedix, Inc. | Date: 2012-08-01
The present invention provides arylamide compounds and methods of making and using them as antibiotics.
PolyMedix, Inc. | Date: 2012-06-21
Aspects of the present invention relate to compounds and methods useful in modulating angiogenesis and methods of treating or preventing diseases associated with angiogenesis by administering a polycationic compound. The present invention relates to methods of use and compositions for inhibiting angiogenesis-mediated disorders in mammals including animals and humans. Additionally, this invention relates to the combined use of polycations with other anti-angiogenesis agents for the treatment of different angiogenesis-mediated disorders. Additionally, those polycationic compounds can be used with various anti-inflammatory and cytotoxic agents as well as with radio-therapeutic agents in cancer patients to prevent and treat tumor growth and metastasis.
PolyMedix, Inc. | Date: 2013-01-18
The present disclosure provides compounds, or pharmaceutically acceptable salts thereof, for killing or inhibiting the growth of a Candida or Aspergillus species or preventing or treating a mammal having candidiasis (oral and/or disseminated) or an Aspergillus infection.
PolyMedix, Inc. | Date: 2012-05-15
The present invention provides methods for treating and/or preventing mucostitis with one or more compounds, or pharmaceutically acceptable salts thereof, disclosed herein, or compositions comprising the same.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 161.38K | Year: 2012
DESCRIPTION (provided by applicant): Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of chemotherapy and radiation therapy for cancer, and represents an important unmet clinical need with 450,000 Americans suffering from mucositis each year. It impacts virtually all patients receiving concomitant chemoradiation therapy for tumors of the mouth and oropharynx. Aside from its devastating symptomatic impact, resulting in opiod-requiring pain and the need for gastrostomy feeding, mucositis is a major driver of adverse health and economic outcomes. The pathogenesis of mucositis is much more complex than previously hypothesized, involving more than a dozen mechanistic canonical pathways mediated by cells within the submucosa, as well as theepithelium. Furthermore, evidence suggests that the oral microflora does not play a primary role in the genesis of mucositis, although secondary infection might influence its course. Despite the prevalence of mucositis in cancer therapy, there is currentlyonly one approved pharmaceutical for the treatment of oral mucositis: palifermin (keratinocyte growth factor-1) and its application is limited to mucositis associated with conditioning regimens for stem cell transplant for the treatment of hematologic malignancies; an indication that accounts for only 4% of the at risk population. Therefore, the care for mucositis i largely palliative and there is an urgent need for new, effective therapies for the broader patient population. Host defense proteins (HDPs)are cationic and amphiphilic components of the mammalian innate immune system that serve as a primary response in the prevention of bacterial infection. We are developing non- peptidic mimics of HDPs, capturing the structural and biological properties ofHDPs within the framework of smaller inexpensive oligomers. These small synthetic oligomers are less expensive to produce, have better tissue distribution than HDPs, and are easier to fine-tune structurally to improve activity and minimize toxicity. Exclusive of their antimicrobial activity, HDPs have been shown to possess immune modulatory and anti- inflammatory activities. Recently, we observed that several of the PMX mimics demonstrate activity in attenuating anti-inflammatory pathways and reasoned thatthese activities could be leveraged into a mucositis intervention. Our hypothesis was borne out by the results of animal studies in which the severity and course of radiation-induced mucosal injury were dramatically altered after topical administration ofthree PMX mimics, including our lead compound PMX30063. The promising activity and observed tolerability of PMX30063, supports a dedicated effort for further preclinical profiling directed towards future clinical development. Accordingly, the overall goals of this Phase 1 proposal are to continue the preclinical development of PMX30063 for an oral mucositis indication by investigating its mechanism of action with a particular focus on anti-inflammatory and immune modulatory activities, optimizing its formulation as an oral rinse and helping to define dosing regimens for human clinical trials. PUBLIC HEALTH RELEVANCE: Oral mucositis is among the most significant, dose-limiting side effects of intensive cancer treatment and is associated with adverse clinical and economic outcomes. It can cause difficulty with speaking, swallowing, and alimentation and radically impair daily functioning and quality of life and may necessitate opioid analgesia, a liquid diet, I hydration and/or total parenteral nutrition and interruption of cancer therapy. Standard management options for mucositis are essentially palliative. We propose to develop a novel topical anti-mucositis therapeutic to ameliorate this pernicious side effect of cancer therapy.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2012
DESCRIPTION (provided by applicant): Malaria is a global disease causing gt 500 million clinical cases and gt 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is crucial to discover new classes of drugs for anti-malarial drug design to combat resistant parasites. We propose that antimicrobial peptides (AMPs) may provide the basis of a novel class of antimalarials. AMPs are an essential component of the innate immune system. AMPs display very broad- spectrum action against bacteria, yeast, fungus by specifically disrupting their membranes rather than targeting proteins. Antiparasitic activities are also reported for a number of AMPs and are thought to kill protozoa by a mechanism similar totheir mechanism of action against bacteria: interacting with plasma membranes, causing excessive permeability, lysis and death. Specificity for the parasite versus host cell is attributed to differences in phospholipid content and the lack of cholesterol in the protozoan membranes. Importantly, the site of action for AMPs is the plasma membrane and not any specific receptors or intracellular protein targets that can easily mutate to escape drug inhibition. Thus, the development of resistance to AMPs is lesslikely to occur. However, while AMPs have good antimicrobial activity, problems with tissue distribution and toxicity have presented obstacles to translating this expensive class of peptides into drugs. PolyMedix has developed series of small non-peptidicmimics of these AMPs (SMAMPs), which have robust, broad- spectrum activity against bacteria and markedly lower toxicity in animals. We propose SMAMPs may provide the basis of a novel class of antimalarials against which resistance will be intrinsically difficult to develop. SMAMPs from PolyMedix were tested and several kill Pl. falciparum parasites in culture having submicromolar IC50s and low cytotoxicity. Importantly, the top hits are active against both chloroquine-sensitive and resistant parasite lines. Our hypothesis is that they act through the perturbation of the food vacuole and possibly other parasitic membranes resulting in the rapid lysis of the food vacuole and parasite death. Membrane targets in bacteria for antimicrobials have been associatedwith a lower likelihood for developing resistance and this will be tested in Pl. falciparum. The goal of this grant is to validate and pursue antimalarial SMAMPs for therapeutic development. The Phase I portion generates proof-of-concept for this class ofcompounds through in vitro and in vivo efficacy testing. The Phase II segment aims to result in a discovery lead therapeutic candidate(s). Targeting parasite membranes using SMAMPs represents a highly innovative and novel approach to treating parasitic diseases and distinguishes this project from others in the field. Malaria is a global disease causing at least 500 million clinical cases and more than 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is paramount to discover new classes of drugs for anti- malarial drug design to combat resistant parasites. We propose to develop novel antimalarial therapeutics using small non-peptidic mimics of naturally-occurring antimicrobial peptides.These therapeutics should prove to be potent, active against resistant parasites and display a low incidence of resistance.