Recent Patents on Anti-Infective Drug Discovery (v.9, #1)

Beta-lactam antibiotics constitute the agents most widely used against bacterial infections worldwide. Hence,the emergence and spread of beta-lactam hydrolyzing enzymes among pathogenic bacteria has proved to be one of the majormedical issues especially when these enzymes inactivate carbapenems together with other beta-lactams. The promptdetection of beta-lactamases is important for therapeutic and epidemiological purposes therefore, various appropriatemethodologies have been developed throughout the last decades. In the present overview, recent patents related to the detectionof beta-lactamases and especially of carbapenemases are discussed.

Background: Vitamin D deficiency and abnormal bone mineral density (BMD) have been reported in HIV patients.We aimed to find out the effects of antiretroviral therapy (ART) on serum vitamin D, parathyroid hormone (PTH)levels, BMD changes and fragility fracture rates in HIV patients.;Methods: We collected information about baseline demography, risk factors for fracture, viral load (VL), CD4 count, serum25-OH vitamin D (n=357), PTH (n=277), phosphate, ionised calcium, creatinine and BMD of spine and hip byDEXA scan (hologic, n=142). Statistical analysis used one-way ANOVA followed by Dunn's multiple comparison tests.;Results Table 1: Total 357 patients, mean age 41.1 (+/- 11.9) years, 249 (66%) black African, 197(52%) females, baselineCD4 count 451 (+/- 184) cells/dl, VL 1.4 log (+/- 1.2) copies/ml, duration of ART 52 (+/- 35) months were includedin the analysis. Serum vitamin D was 15.3 (+/- 11.0) ng/ml, PTH (intact) 5.5 (+/- 3.9) pmol/l, corrected calcium 2.13 (+/-0.9), phosphate 1.0 (+/- 0.2) and creatinine was 73.4 (+/- 21.1) mmol/l. Ninety four (66%) patients had abnormal BMD(T-score of spine or hip or both ≤ 1.0). Vitamin D levels were deficient (< 30 ng/ml) in 297 (78.7%) and PTH was high(>4.1 pmol/l) in 177 (64.8%) patients. Of 91 (30.9%) patients who had vitamin D levels below 10.0 ng/mL, PTH was highin 70 (n=91, 76.9%) and abnormal BMD in 50 (n=61, 75.4%) patients. Thirteen patients (3.2%) had possible fragilityfractures. Tenofovir (TDF) users had higher PTH (P=0.002) and lower BMD of spine (0.01) and hip (0.002) and efavirenz(EFV) users had lower vitamin D (0.01) levels. On multivariate analysis including all significant variables, female sex(OR 1.5 CI 1.3-5.9), age over 40 years (OR 1.2 CI 0.9-5.1) and TDF use (OR 1.9 CI 1.6-6.9) were associated with abnormalBMD of hip but not spine.;Conclusion: Female patients over 40 years old on tenofovir containing regimens may have increased risk of BMD lossfrom hip. Whether Vitamin D replacement will prevent further bone loss needs further work.

Recent Advances in the Development of Anti-Infective Prophylactic and/or Therapeutic Agents Based on Toll-Like Receptor (TLRs) by Elena C. Junquera, Lourdes Mateos-Hern&#225;ndez, Jose de la Fuente, Jose M.P. de la Lastra (14-24).
Toll-like receptors (TLRs) are key players in innate immunity. They are able to sense different microorganismsranging from protozoa to bacteria, fungi or viruses. Innate immune responses can directly influence adaptive immune responses.Therefore, TLRs are considered as relevant targets for therapeutic applications in immune diseases: such as autoimmunedisorders, allergy, sepsis, and cancer. We here review the recent patents based on the modulation of the toll-likereceptors to develop anti-infective (prophylactic and/or therapeutic) agents.

Current Status of Anti-Tuberculosis Therapy: A Patent Analysis by Ananya Singh, Aanchal Budhraj, Aastha Shrivastava, Akshaya Satyavana, Aman Gupta, Money Gupta, Gulshan Wadhwa, Sanjeev K. Sharma, Chakresh K. Jain (25-40).
Abstract: Affecting more than one third of the world population, tuberculosis remains one of the world's most dreadfuldiseases, with no easy cures. Mycobacterial infestation and the evasion of host immune response are significantly responsiblefor the emergence of pulmonary tuberculosis. Mycobacterium tuberculosis, a weak gram positive, facultative aerobecolonizes in respiratory regions rich in oxygen reserves. Up regulation of CR and MR expression and function due to signalingby LAM results in electing immuno regulatory cytokines IL-4, IL-8 and Th2. Binding of NF-κB complex withmRNA prevention, due to mutation of leucine zipper domain of IK, inhibits the activation of cytokines and receptor molecules.Mechanism of energy generation by conversion of ADP to ATP, initiated by utilizing intermediary and/or end productsof carbohydrate, amino acid or fatty acid catabolism is essential in approximating potential drug targets forelimination of the bacterium. A few improved diagnostic techniques have been evaluated over the last few years like InterferonGamma Relese Assays, Nucleic Acid Amplification tests etc. of which most have certainly proven to facilitatespecific detection of TB. Drugs like Rifampicin, Isoniazid etc. have also shown great curing effects on TB patients.;Further research is required for better understanding of mechanism of pathogenesis and multiple drug resistance issues fordeveloping the effective therapeutics and diagnostics against TB. The paper focuses on the effective diagnostics andtherapeutics applications for tuberculosis prevention and cure based on recent patents and their analysis.

Which Patients have Greatest Need for Elvitegravir/Cobicistat/ Emtricitabine/TenofovirDF-Based Therapy? by Antonio Di Biagio, Roberta Prinapori, Lucia Taramasso, Giulia Gustinetti, Laura Sticchi, Bianca Bruzzone, Claudio Viscoli (41-51).
Elvitegravir/cobicistat/emtricitabine/tenofovirDF (EVG/COBI/FTC/TDF) is the new single-tablet, fixed-doseformulation containing an integrase strand transfer inhibitor recently approved as antiretroviral treatment. In this paper weanalysed its use and advantages in naïve and experienced HIV-infected patients and we focused on special populations inwhich EVG/COBI/FTC/TDF could be a suitable option. Furthermore the manuscript reports the recent patent of EVGwhich may have an influence on the management of HIV-infected patients in the next future.

Patent Prospects Toward Therapeutics and Diagnostics of Anthrax by Rashi Chauhan, Gulshan Wadhwa, Sanjeev K. Sharma, Chakresh K. Jain (52-61).
Anthrax is one of the deadly infectious disease as documented in the CDC website. In spite of the availabilityof appropriate antimicrobial agents, the mortality related with the anthrax remains high. The pathogenicity of B.anthracisis mainly accredited to the two foremost components: toxins and capsule. Virulence component of B.anthracis includesprotective antigen (PA) which plays a vital role in pathogenesis, virulence protein edema factor (EF) and lethal factor(LF). This search for novel therapeutic strategies that attack the proteins involved in the pathogenesis of anthrax and maypotentially supplement antimicrobials being investigated. Currently, extensive attempts are in progress to develop novelhelpful therapies to all of the virulence components: lethal factor, protective antigen, edema factor and the capsule of B.anthracis. This review discusses the potential anthrax therapeutic, prophylactic measures and diagnostic applicationsbased on recent patents' prospects.

Survey of Epstein Barr Virus (EBV) Immunogenic Proteins and their Epitopes: Implications for Vaccine Preparation by Julius Rajcani, Kalman Szenthe, Ferenc Banati, Susan Szathmary (62-76).
The Epstein-Barr virus (Human herpesvirus 4) encodes approximately 80 proteins, from which 15 possess atleast 90 antigenic epitopes. Many of them stimulate the T cell receptors (TCR), but a few interact with the B cell receptors(BCR). Activation of B-cells and subsequent antibody production has not only been related to at least 3 envelope glycoproteins(mostly gp350) but also to latency associated membrane proteins (LMPs). The majority of EBV epitopes (over80) inducing either cytotoxic and/or helper T lymphocytes were located on non-structural and/or latency associated polypeptides.The former interaction mediated by CD8plus/T cells is restricted by the HLA I molecules, predominantly ofHLA-A subclass. In acute infectious mononucleosis (IM) patients (about 40 %) a considerable proportion of HLA B8 restrictedCTL reactivity is directed against a single peptide (RAKFKQLL) of transactivator protein BZLF1/Zta. The EBVvaccines designed so far fall into two categories: those preventing any kind of infection (including prophylaxis of EBVassociatedmalignancies) and those designed for therapeutic purposes (to be used in subjects already infected). Preventivevaccines protecting against acute disease (such as IM) contain, as a rule, the gp350 polypeptide(s) encoded by the BLLF1gene. Vaccines destined for tumor prevention rather consist of peptides derived from latency associated nuclear proteins(EBNA 2, 3 and 6) and/or from oncogenic latent membrane proteins (LMP1/LMP2a). Whereas the former generates antibodiespreventing virus entry, the latter would potentiate the cell mediated response. In addition to recently described andpurified individual recombinant immunogenic EBV polypeptides and/or their mixes, new perspectives were opened byconstruction of random overlapping strongly immunogenic scrambled polypeptide(s). Further novel approaches are basedon carefully selected antigenic peptides (oligopeptides) coming from both, structural as well as non-structural or latencyassociatedproteins bound to suitable carriers. Any constructs based on latency-associated proteins might be useful eitherfor immunoprophylactic therapy following bone marrow and/or heart transplantations or for the prevention of EBVrelatedtumors such as lymphomas and nasopharyngeal carcinoma. Due to the growing importance of the selected immunogenicepitopes as future vaccine components, at least the half of them has been patented not only as the natural aminoacid sequence but also in different variations.