Recent Patents on Anti-Infective Drug Discovery - Volume 1, Issue 2, 2006

Access to an array of cytokines and synthetic immunomodulators represents a significant milestone in the development of effective therapies for infectious diseases. Several recombinant human cytokines, including interferons and colony-stimulating factors, are licensed and being widely used in clinical practice in patients. The identification of the essential role of coreceptors for the entry of HIV into the host cell has focused attention on chemokines as important targets for pharmacological intervention and several new compounds possessing therapeutic potential as inhibitors of chemokine receptors have been advocated. Diverse combinations with pegylated interferons and other cytokines for the treatment of various viral infections, including hepatitis B and C, have been proposed. Significant advances have been achieved on compounds exhibiting cytokine inhibitory properties of value for new treatments of infectious and inflammatory diseases. Important developments and current trends in cytokine biology and therapy are highlighted in this review. Novel strategies based on the engineering of cytokines and inhibitors are poised to revolutionize therapeutic options in the coming decades.

Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogs of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others, new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential.

The number of organosulfur compounds being patented has been growing. A wide variety of these organosulfur compounds, whether naturally occurring or synthetic, exhibit antibacterial properties. Mechanistically, organosulfur groups can act as metal chelators, powerful nucleophiles or electrophiles depending on the local environment in which a given reaction occurs. In this review of the patent literature from 1999-2005, the reliance of these compounds on the reaction of the sulfur moiety with its biological target(s) will be discussed with regards to activity, specificity, and antimicrobial spectrum.

Microbial pathogens with resistance to conventional drugs are a problem of global proportions and may be viral such as HIV, bacterial as in the case of MRSA or eukaryotic as seen with the malarial parasite Plasmodium falciparum. In response, photodynamic antimicrobial chemotherapy (PACT) has been developed, which is the delivery of a non-toxic photosensitiser (PS) to the site of a microbial infection. When taken up by the pathogen, illumination of the PS by light at an appropriate wavelength can lead to inactivation of the pathogen through the production of highly reactive free radical species, which induce oxidative damage to lipid, proteins and DNA / RNA, and / or adduct formation between the PS and these microbial biomolecules. Here the photochemical and photophysical steps underlying PS antimicrobial action along with the desirable electronic and physiochemical properties of PS are briefly reviewed. The therapeutic uses of PS are then illustrated with reference to a number that have featured in recent patents, including: The induction of endogenous PS by aminolevulinic acid; phenothiazinium based PS, which are the most studied of PACT agents, psoralens and organorhodium complexes.

Ribosomally synthesized antimicrobial peptides have very wide killing spectra and bacterial resistance to these peptides seems to be a rare phenomenon. Indolicidin is a ribosomally synthesized antimicrobial peptide that served as a template to omiganan, which is in development for the prevention of catheter-related bloodstream infections; clinical trials also proved its efficiency against acne vulgaris. Omiganan is the most advanced molecule in the front line of clinical applications of antimicrobial peptides. The mode and site of action of omiganan are not yet settled although its interaction with membranes is known to play a fundamental role. The biochemical and biophysical foundations for the action of indolicidin and its analogues are reviewed in this paper, as well as the clinical application of omiganan. The in vitro efficiency tests and the outcome of clinical trials are addressed. Altogether, despite the very specific use of omiganan as a topical antibiotic, it has the potential of being a pioneer of a new generation of antibiotics that carry the promise of ending the multi-resistance problem.

Infectious diseases have haunted human populations for millennia. Still we are struggling with this scourge because of multiple complexities. These include the emergence of new pathogenic species due to mutations owing to the naturally ticking evolutionary clock. In addition, under the selective pressure of existing powerful antibiotics, which have been helpful in effectively managing many infectious diseases for a long time, resistant species arise quite commonly. Therefore, there is always an urgent need to invent new strategies to fight new strains of these pathogens. We review here some important patents that have been licensed for drug development pertaining to protease and kinase inhibitors. Instead of being comprehensive, we have been selective in our choices. We apologize to those whose patents we could not cite. Our goal is to inform public at large of the new inventions in the pipeline and their status toward development of these technologies as drugs in the clinic.

Anti-infective agents are used to treat disorders caused by bacteria, viruses, protozoa, worms, and fungi (including yeast). They are substances used on humans, animals and plants that destroy harmful microorganisms or inhibit their activity. In this mini-review, we are focusing on novel development of anti-fungal agents that have been published during the past two years. Fungi are eukaryotic microorganisms comprising over 100,000 species. Nearly 40% of all deaths from hospital-acquired infections were caused by fungi over the past 20 years. An effective anti-fungal agent is toxic to the pathogenic fungi, but not to the host. Treatment of fungi diseases, however, is often limited because antifungal agents are often toxic to the mammalian or plant host. In this review, 11 patents were chronologically and unbiasedly selected from 454 that fit the criteria out of a 4,716,037 patents search. These patents highlight the novel approaches that have been used to tackle difficult fungi. The strategies include targeting key fungal structures and metabolic pathways, developing manufacturing processes of anti-fungal reagents, unique membrane interfering fungicides, and plant and insect defensins.

Conventional chemical preservatives used in prevention of food spoilage caused by microorganisms have shown adverse effects and found to be of low effectiveness. This challenging situation stimulated research to find alternatives. As a result, numerous natural product-based compounds have been patented for use as antimicrobial food preservatives. These compounds comprise phenolic and non-phenolic ones. The phenolic agents include mainly those composed of a single aromatic ring and flavonoid-derived molecules. The phenolic compounds display multifunctional activities, while the nonphenolic do not. Polyhydroxybenzene derivatives exhibit high potential as effective antimicrobial or as antioxidants agents. Among the later category is 1,2,3,4-tetrahydroxybenzene (THB). THB has been recently patented as a highly effective antimicrobial and antioxidant agent. It showed significant and broad-spectrum antimicrobial activity versus a wide range of grampositive, gram-negative bacteria, yeasts, and fungi, including pathogenic and non-pathogenic organisms. Its effectiveness as an antioxidant is equal or superior to commonly used antioxidants such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Production of 1,2,3,4-tetrahydroxybenzene was accomplished efficiently by adopting a bioengineered synthesis, that is recently disclosed. In addition, there is also a patented simple chemical method.

Raf proteins are key components in the signal transduction of the Ras/Raf/MEK/ERK pathway, which is pivotal in oncogenesis, tumor cell malignancy, viral infection, neuronal degeneration, and lymphocyte activation. A number of gain-of-function mutations of Raf genes have been detected in various cancer cells. Consequently, Raf as an anticancer target has been intensively investigated. Numerous small-molecule Raf-inhibiting compounds have been reported in the literature and in patent applications. One of such compounds, the urea derivative Bay 43-9006, has been subjected to the most extensive clinical trials on cancer, including phase III trials, and results to date indicate that this agent can provide clinical benefit without obvious toxicity. Small-molecule Raf inhibitors have also been evaluated preclinically for treatment of viral infection, neuronal degeneration, and inflammatory disease. Thus, small molecule inhibitors of Raf may have broad applications in addition to cancer therapy.

Human respiratory syncytial virus (HRSV) is a major respiratory viral pathogen causing moderate to severe upper and lower respiratory tract infections in all ages and across a wide range of patient populations. There are no currently approved vaccines and although a number of candidates are in various stages of development, the challenges are quite substantial. Presently, only a single agent is approved for HRSV prophylaxis, and therapeutic treatment options are severely limited and ineffective, particularly in the infant population. Antibody prophylaxis is restricted to use in populations at high-risk for hospitalization (infants under 35 weeks gestational age, infants with chronic lung disease, and infants with congenital heart disease). Aerosol administration of the guanosine analog ribavirin has been approved for the treatment of severe HRSV LRTI in both children and mechanically ventilated patients; however, there is still debate over its overall benefit and the risks associated with its use. Current therapy for those hospitalized due to HRSV is supportive. As such, there is great medical need for the development of agents to prevent and treat HRSV infections in all populations. Interestingly, many of the discovered agents against HRSV, both neutralizing antibodies and small molecules inhibitors, target the viral fusion (F) glycoprotein. In particular, three distinct chemical classes as exemplified by JNJ- 2408068, VP-14637, and BMS-433771, which appear to block conformational intermediates of the viral fusion protein are reviewed.

Since the human immunodeficiency virus was identified as etiological agent of the acquired immunodeficiency syndrome, great advances have been accomplished in the therapeutic field leading to reduced morbidity and mortality among infected patients. However, the high mutation rate of the viral genome generates strains resistant to multiple drugs, pointing to the importance of finding new therapeutic targets. Among the HIV structural genes, the POL gene codes for three essential enzymes: reverse transcriptase, protease, and integrase; nineteen of the twenty drugs currently approved by the Food and Drug Administration to treat this viral infection, inhibit the reverse transcriptase and the protease. Although intense research has been carried out in this area during the last 10 years, HIV integrase inhibitors are not yet approved for clinical use; however the fact that presence of this enzyme is a sine qua non for a productive HIV life cycle joined to its unique properties makes it a promissory target for anti-HIV therapy. Many compounds have been claimed to inhibit integrase in vitro; however, few of them have proven to have antiviral activity and low cytotoxicity in cell systems. Diketoacid derivatives are the most promising integrase inhibitors so far reported. Initially discovered independently by Shionogi & Co. and the Merck Research Laboratories, these compounds are highly specific for the integrase with potent antiviral activity in vitro and in vivo, and low cytotoxicity in cell cultures. Some of these compounds have recently entered clinical trials. Due to the high relevance of integrase inhibitors, and specifically of diketoacid derivatives, we review the latest findings and patents in this important field of research.