Biomedical subjects

W Haq

Publications and source records attributed to W Haq.

At least 19 recordsLinked to original sources

PubMed2007

Synthesis and antimalarial activity of side chain modified 4-aminoquinoline derivatives.

A new series of side-chain modified 4-aminoquinolines have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 6, 11, 12, and 19 exhibited superior in vitro activity compared to chloroquine. Selected compounds 6, 12, and 19 exhibited significant suppression in the in vivo assay. These analogs form a complex with hematin and inhibit the beta-hematin formation, suggesting that this class of compounds act on a heme polymerization target.

Aminoquinolines↗

PubMed2006

Design, synthesis and antimalarial activity of a new class of iron chelators.

Iron is crucial for many biochemical reactions involved in the growth and multiplication of the malaria parasite Plasmodium falciparum. There are many reports indicating that the iron chelators have antimalarial activity in vitro, in vivo and in human studies. However, these compounds suffer from a number of serious problems such as limited membrane permeability, short half-life and require long subcutaneous infusions. To circumvent these drawbacks we have designed a new class of iron chelators, wherein EDTA is tethered to 4-aminoquinoline. Here 4-aminoquinoline scaffold is used as a carrier to penetrate biological membrane and facilitate targetting the compounds to acidic food vacuole of the parasite. This study describes the synthesis of novel iron chelators and their in vitro antimalarial activity against P. falciparum strain of NF-54. The calculated LogP values of these compounds suggest the importance of lipophilicity for the antimalarial activity. The EDTA esters are more active than the corresponding acids. The biophysical studies suggest that these compounds may inhibit the parasite growth by iron chelation mechanism.

Aminoquinolines↗

PubMed2005

Immunomodulatory activity of analog of muramyl dipeptide and their use as adjunct to chemotherapy of Leishmania donovani in hamster.

In search of a potent immunomodulator to be used as an immunoprophylactic agent and as adjunct to chemotherapy against Leishmania infection, two analogs of muramyl dipeptide, viz. N.Ac-norMur-MeVal-D-isoGln (86/448) and N.AcMur-Acc-D-isoGln (89/729) were evaluated for desired activity. Effect of these peptides on cell mediated and humoral immunity was studied by immunizing the peptide treated mouse with sheep red blood cells (SRBC) and determining HA-titer, plaque forming cells assay and delayed type of hypersensitivity (DTH) response after 4-5 days. Both the peptides stimulated cell mediated immunity (CMI), humoral response as well as macrophage function in terms of super oxide anion (O2-) and nitric oxide (NO) generation. Mitogen induced lymphocyte proliferation and production of IL-2 and INF-gamma increased while that of IL-4 and IL-10 decreased by both the peptides showing a typical Th1 type response. After establishing the immunostimulatory activity, these peptides were evaluated for immunoprophylactic efficacy as well as for use as adjunct to chemotherapy with stibanate (SSG) against Leishmania donovani infection in golden hamster. These peptides were found quite effective in both the modes. In adjunct use the treatment may require lower dose of SSG and thereby reduce the chances of drug toxicity.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Tuftsin-bearing liposomes as antibiotic carriers in treatment of macrophage infections.

Tuftsin is a tetrapeptide (Thr-Lys-Pro-Arg) that specifically binds monocytes, macrophages, and polymorphonuclear leukocytes and potentiates their natural killer activity against tumors and pathogens. The antimicrobial activity of this peptide is significantly increased by attaching at the C-terminus a fatty acyl residue through the ethylenediamine spacer arm. This activity is further augmented by incorporating the modified tuftsin in the liposomes. The tuftsin-bearing liposomes not only enhance the host's resistance against a variety of infections but also serve as useful vehicles for the site-specific delivery of drugs in a variety of macrophage-based infections, such as tuberculosis and leishmaniasis.

Animals↗

PubMed2004

Synthesis and antimicrobial activity of erythromycin-A oxime analogs.

A series of erythromycin-A oxime ether as well as esters have been synthesized. Ether derivatives were synthesized through the epoxy ether intermediate of erythromycin-9-oxime, followed by opening of the epoxy linkage through various amines, whereas esters have been prepared through DCC mediated protocol. These derivatives have been evaluated for antibacterial activity and found to be as active as erythromycin-A.

Anti-Bacterial Agents↗

PubMed2004

Adjunct effect of immunostimulating hexapeptide analogous to human beta-casein fragment (54-59) to sodium stibogluconate against experimental visceral leishmaniasis.

Visceral leishmaniasis (VL) is a major public health problem in many tropical countries of the world. The available chemotherapeutics require parenteral administration and have other limitations like cost, toxicity, variable efficacy or restricted supplies. There is no effective treatment for immunosuppressed patients with leishmaniasis- HIV co-infection. Hence, new therapies, that are effective when treatment with the currently available drugs fails, must be developed. One of the major strategies for effective and safe treatment of leishmaniasis and other infectious diseases, in the last decade, involves the use of immunomodulators as adjunct to chemotherapy. In this context, we studied the immunomodulatory activity of a hexapeptide Val-Glu-Pro-Ile-Gly-Tyr (CDRI compound 89-215) corresponding to (54-59) fragment of human beta-casein in mice and its efficacy in adjunct chemotherapy with SSG using L. donovani/hamster model. The hexapeptide was found to enhance both humoral and CMI responses. In animal model the hexapeptide per se showed no antileishmanial activity. However, when given alongwith suiboptimal dose of SSG, it enhanced the efficacy of SSG from 24% to 80%. The activity was very close to the efficacy (85%) recorded for curative dose of SSG. Adjunct chemotherapy with immunomodulator in visceral leishmaniasis appears to be a fruitful preposition.

Adjuvants, Immunologic↗

PubMed2003

Generating neutralizing antibodies, Th1 response and MHC non restricted immunogenicity of HIV-I env and gag peptides in liposomes and ISCOMs with in-built adjuvanticity.

For enhancing immunogenicity and develop vaccine strategies using peptide based constructs against HIV-1, a chimeric peptide containing V3 loop and transmembrane sequence of gp41 with two glycine motifs as spacer was constructed. The V3-gp41, gp41 peptide and p17 and p24 peptides separately or in a cocktail were entrapped with or without MA729 as an immunoadjuvant in liposomes or ISCOMs. The immunogenicity, antigen induced T-cell proliferation and cytokine profiles of various formulations were studied in four different inbred strains of mice of H-2d, H-2b, H-2k and H-2q haplotypes, keeping alum as a control adjuvant. Both liposomes and ISCOM preparations elicited high titer and long lasting antibody response (60 days and above). When compared to the alum formulation, the liposomes co-entrapped with MA729 produced high antibody levels, comparable with that induced by ISCOMs. Peptide in alum, liposomes and ISCOMs enhanced both antigen specific IgG2a and IgG2b isotypes and high T-cell stimulation index. Peptide formulations also induced antibodies with high affinity and in vitro neutralizated the formation of HIV-1 syncytia. T-cell supernatants contained high levels of IFN-gamma and IL-2. Thus formulation in these adjuvants induced a predominant Th1 like response with MA729 as a versatile novel delivery vehicle for stimulating the appropriate arm of the immune response that can selectively modulate MHC class I or MHC class II response. The above peptide can be of wide vaccination interest as a means to improve immune responses to several other HIV-1 antigens and may serve as candidates for vaccine development.

Journal Article↗

PubMed2003

Reversal of T cell anergy in leprosy patients: in vitro presentation with Mycobacterium leprae antigens using murabutide and Trat peptide in liposomal delivery.

Mycobacterium leprae, the causative agent of leprosy resides and multiplies within the host monocytes and macrophages, thereby evading host immune system. Cell-mediated immune response (CMI) plays a vital role as evidenced from the high CMI in BT/TT (borderline and tuberculoid) patients and conversely low in BL/LL (borderline and lepromatous) patients. In the present study, an attempt was made to immunomodulate the anergized T cells of lepromatous leprosy patients by presenting the mycobacterial antigen in combination with T cell adjuvant, murabutide (active analog of muramyl' dipeptide, MDP-BE) and a Trat peptide (T cell epitope of Integral membrane protein (Trat) from Escherichia coli) in particulate form (liposomes) or soluble form (media). PBMNC of normal, BT/TT and BL/LL were stimulated in vitro with five mycobacterial antigens (Ag) in the following formulations, Ag, Ag+murabutide, Ag+murabutide+Trat peptide either in liposomes or in medium. All the five antigen(s) when delivered in liposomes containing murabutide and Trat peptide showed a very high lymphoproliferative response (p<0.001) in all the three groups. IFN-gamma and IL-2 were significantly (p<0.001) high in these culture supernatants compared to IL-10 and IL-4 confirming a shift from CD4+Th2 to Th1 response in leprosy patients with particulate mode of antigen presentation. Interestingly, PBMNC derived from lepromatous patients also showed consistent T cell proliferation with all the formulations. Further, the mechanism of liposomal processing of antigens was studied using different inhibitors that interfere at different stages of antigen presentation. Results indicate that this study may pave way for an immunotherapeutic approach for reverting the anergic T cells of lepromatous patients to proliferating T cells with the release of Th1 cytokines thereby restoring the CMI response in these patients.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2003

Use of tuftsin bearing nystatin liposomes against an isolate of Candida albicans showing less in vivo susceptibility to amphotericin B.

In the present study, we evaluated tuftsin bearing nystatin liposomes for their potential against an isolate of Candida albicans (C. albicans) showing less in vivo susceptibility to amphotericin B (Amp B). The liposomised-Amp B in higher doses was found to be effective in elimination of less susceptible strain of C. albicans (C. albicans JMCR) in Balb/c mice, but may not be recommended due to toxicity constraints. On the other hand, liposomal nystatin was shown to possess higher efficacy as compared to that of Amp B, and was pertinent in treatment of C. albicans JMCR strain. The data of present work reveals that the incorporation of nystatin in tuftsin-bearing-liposomes results in a significant increase in its efficacy against experimental murine candidiasis. Interestingly, the pre-treatment of animals with liposomised-tuftsin prior to challenge with C. albicans infection was more effective in elimination of the pathogen from host and shows an advantage in prophylactic perspectives.

Adjuvants, Immunologic↗

PubMed2003

Immunomodulator tuftsin augments antifilarial activity of diethylcarbamazine against experimental brugian filariasis.

In the present study, we evaluated the potential of an immunomodulator tuftsin in increasing the efficacy of liposomised diethylcarbamazine (DEC) against experimental filarial infection of Brugia malayi. The liposomised form of DEC, when used at sub-optimal dose of 25 mg/kg body weight, successfully eliminated filarial parasite from systemic circulation in animals inflicted with B. malayi infection. However, the formulation was effective upto 60 days post infection only, followed by recurrence of the infection. In contrast, the co-administration of liposomal formulation of DEC along with an immunomodulator tuftsin was found to be competent enough to suppress microfilarial stage of parasite till 90 days post treatment. Interestingly, tuftsin bearing DEC liposomes were found to be effective against adult parasite as well.

Adjuvants, Immunologic↗

PubMed2003

Inhibition of anti-CD3 and interleukin-2 stimulated T lymphocyte proliferation by peptidomimetic opioid compound.

In continuation to our earlier studies with peptidomimetic opioid compounds, we have further investigated immunosuppressive properties of one of our peptidomimetic compound (Tyr-NH-CH2-CH2-O-Phe-NH2) using peripheral blood mononuclear cells (PBMCs) of healthy volunteers. Peptidomimetic compound was evaluated for its effect on anti-CD3 and recombinant human interleukin-2 (rhIL-2) stimulated lymphocyte proliferation in vitro and lipopolysaccharide (LPS) induced activation of mitogen activated protein kinase (MAPK, pp42/44) in mouse macrophage cells (RAW 264.7). Our results show the immunosuppressive potential of synthetic peptidomimetic compound. This compound significantly inhibited anti-CD3 and rhIL-2 stimulated lymphocyte proliferation in vitro. However, this peptidomimetic compound did not show any effect on LPS induced MAPK activation. These observations suggest that above peptidomimetic compound has potential to inhibit immune responses mediated by lymphocytes.

Animals↗

PubMed2002

Inhibition of antigen specific lymphocyte proliferation and cytokine stimulation by peptidomimetic opioid compound.

In sequel to our preliminary observations with peptidomimetic opioid compounds, we have further investigated immunomodulatory activity of one peptidomimetic compound (Tyr-NH-CH2-CH2-O-Phe-NH2) with peripheral blood mononuclear cells (PBMCs) of healthy volunteers/tuberculosis patients. This peptidomimetic compound was evaluated for its effect on purified protein derivative (PPD) stimulated lymphocyte proliferation in vitro, production of Th1 and Th2 cytokines by ELISA and ribonuclease protection assay. Our study shows the immunosuppressive potential of above synthetic peptidomimetic compound. This compound inhibited PPD stimulated human lymphocyte proliferation and this inhibition was reversed by opioid receptor antagonist, naloxone. Its immunosuppressive effect was further demonstrated by inhibition of interleukin-9 (IL-9), IL-10 but failed to influence IL-2, IL-15 and interferon-y (IFN-gamma) in PPD stimulated human PBMCs.

Animals↗

PubMed2002

Immunomodulation by biphalin, dimeric synthetic opioid peptide, and its analog.

The opioid pentapeptides called enkephalins were originally described as the endogenous ligands for the opioid receptors. Although their precise physiological significance still remains elusive, the enkephalins have been reported to exhibit analgesic, antidepressant, antianxiety and anticonvulsant activities. In addition, enkephalins have also been shown to act as immunomodulator. The first generation of dimeric peptides was derived from enkephalins. Biphalin [(Tyr-D-Ala-Gly-Phe-NH)2] is a bivalent opioid analog containing two tyrosine residues. We have evaluated the immunomodulatory properties of biphalin and its analogs in various in vitro tests. We report that biphalin and one of its analogs [Tyr-D-Ala-Gly-Phe-NH.NH-Phe(p-Cl)-H] stimulate human T cell proliferation, natural killer (NK) cell cytotoxicity in vitro and interleukin-2 (IL-2) production. Biphalin and its analog also released chemokine like factor in the culture supernatant that was responsible for increased chemotaxis of monocytes. Furthermore, these peptides inhibited tumor necrosis factor (TNF-alpha) production in lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) and nitric oxide (NO) production in mouse macrophage cells, RAW 264.7. Our observations suggest immunomodulatory property of biphalin and its analog.

Adjuvants, Immunologic↗

PubMed2001

Modulation of the humoral response to repeat and non-repeat sequences of the circumsporozoite protein of Plasmodium vivax using novel adjuvant and delivery systems.

In the use of sub-unit vaccines, it is important to identify the protective epitopes and to generate the optimal immune response by using appropriate immuno-modulatory adjuvants and/or delivery systems. The main aim of the present study was to generate an MHC-non-restricted immune response against one promising vaccine candidate, the circumsporozoite protein (CSP) of Plasmodium vivax. Four synthetic peptides were chosen: three repeat-region sequences (AA, DA and ANG) and a putative T-cell epitope extended from a conserved region (region II) containing a hepatocyte-binding region (HBP). The humoral response against each peptide was studied in outbred mice and three strains of inbred mice (with different genetic backgrounds). Delivery of each peptide in microspheres or inclusion of a bio-active casein-fragment analogue as adjuvant with alum/liposome delivery considerably enhanced the humoral response against the peptide (when compared with the response to the peptide delivered in alum alone). The maximal immune response was observed when the peptide was delivered in microspheres, with no booster doses required; the antibodies raised against peptide delivered with adjuvant or in modulatory delivery vehicles had two-to five-fold lower binding affinities. The predominant IgG isotypes elicited using microspheres or adjuvant with alum/liposome delivery were IgG(2a)/IgG(2b) and/or IgG(1). Importantly, conjugation of HBP to the B-cell repeat peptides increased the titres of peptide-specific antibodies, especially of antibodies against the supposedly cryptic HBP. Delivery of a mix of all four peptides in microspheres elicited an intense immune response in outbred mice, indicating that such a delivery system efficiently presents the peptides to the immune effector cells. That antibodies in the anti-peptide sera bound strongly to air-dried sporozoites of P. vivax was confirmed by immunofluorescence. The present results, based on the use of individual peptides or a conjugate or cocktail of the peptides, highlight the utility of the casein-fragment analogue as an adjuvant, when used with alum/liposome delivery, and also demonstrate the potential of microspheres as a single-shot delivery system for sub-unit peptides.

Analysis of Variance↗

PubMed2001

Inducing a cell-mediated immune response against peptides of the Plasmodium vivax circumsporozoite protein.

An attempt was made to generate an unrestricted cellular immune response against peptide antigens of the circumsporozoite protein (CSP) of Plasmodium vivax. The peptides used represent the repeat-region sequences of the type-I variant (AA and DA) or type-II variant (ANG) and the conserved region (region II) containing the hepatocyte-binding region extended to include a T-cell epitope (HBP). The study was conducted in outbred mice and two genetically unrelated inbred strains of mice. Spleen cells, recovered from mice that had been primed either with one peptide or a conjugate formed of HBP linked to one of the repeat-region peptides, were pulsed in vitro with varying amounts of individual peptides/conjugates, both in soluble and particulate form (with and without a human beta-casein bio-active fragment analogue as adjuvant). In the tests using the cells from the mice primed with an individual peptide(s), HBP showed a high proliferation index, and the repeat-region peptides, especially AA, showed T-cell activity in at least one of the mouse strains studied. In vitro, higher concentrations of the free peptides than of liposomal preparations of the peptides had to be used to elicit the optimal proliferation of the cells from each strain of mice. Interestingly, the cells from the conjugate-primed mice showed enhanced proliferation (compared with that observed in the cells from mice primed with individual peptides) when stimulated with each component, and especially the repeat-region sequence, of the relevant conjugate. In such cases there was no evidence of restriction of the immune response by the major histocompatibility complex. The major secreted cytokines were found to be from CD4(+) Th1 (interferon-gamma and interleukin-2), with relatively low levels of the Th-2 cytokines interleukin-4 and interleukin-6. The delivery of cohered 'B-T' peptide(s) sequences from the same protein, ideally with an immunostimulatory adjuvant or as a liposomal preparation, should greatly enhance the cell-mediated immune response and should improve clearance of mosquito-inoculated P. vivax sporozoites.

Analysis of Variance↗

PubMed2001

Immunomodulation by opioid peptidomimetic compound.

OBJECTIVE: As a follow-up to our earlier studies on immunomodulation with opioid peptides, we synthesized and evaluated immunomodulatory activity of four peptidomimetic compounds, i.e. Tyr-NH-C(Me)(2)-CH(2)-O-Phe-NH(2 )(1), Tyr-NH-C(6)H(5)-(o)-CH(2)-CH(2)-O-Phe-NH(2) (2), Tyr-NH-CH(2)-CH(2)-O-Phe-NH(2) (3) and Tyr-NH-CH(D-Et)-CH(2)-O-Phe-NH(2) (4). METHODS: These compounds were synthesized in solution phase and evaluated for their immunomodulatory properties in vitro by mixed lymphocyte reaction (MLR), proliferation of opioid receptor-expressing cells, production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide. RESULTS: This study shows the immunosuppressive potential of synthetic peptidomimetic compound 3. This compound inhibited two-way MLR and suppressed the proliferation of the mu-opioid receptor expressing human embryonic kidney cells HEK 293 in vitro. Inhibition of MLR by compound 3 was reversed by naloxone (opioid receptor antagonist) and beta-funaltrexamine hydrochloride (mu-opioid receptor antagonist). The immunosuppressive effect of compound 3 was further demonstrated by inhibition of TNF-alpha and nitric oxide production in lipopolysaccharide-stimulated human PBMCs and mouse macrophage cells RAW 264.7, respectively. CONCLUSION: These observations suggest that compound 3 inhibits MLR through mu-opioid receptor present on cells.

Animals↗

PubMed2001

Enhanced immunostimulant activity and protective effect of a synthetic lipopeptide after liposomization against Plasmodium berghei infection in mice.

The immunostimulant activity of non-pyrogenic, sugar-free immunomodulator lipopeptide, Ala-D-Glu(Gly-Lys-CO.C11H23)-NH2 (comp. no 84/201), and its liposomized formulation has been studied. Liposomization of this lipopeptide significantly enhanced its antigen specific as well as nonspecific immune responses, as compared to the free lipopeptide. The liposomized formulation of lipopeptide significantly stimulated both the antibody and delayed-type hypersensitivity responses in Balb/c mice, and also enhanced nonspecifically the macrophage migration index, phagocytic activity and incorporation of 14C glucosamine in peritoneal macrophages of the mice that received pretreatment with this preparation. Further, the mice that received pretreatment with the liposomized preparation strongly resisted lethal P. berghei infection and consequently survived for longer period of times. These results indicate that liposomization of the compound no 84/201 significantly improves its ability to enhance not only antigen-specific immune response but also the nonspecific host's resistance against infections.

Adjuvants, Immunologic↗

PubMed2000

Antisense peptide interactions studied by electrospray ionization mass spectrometry.

Non-covalent interactions between met- and leu-enkephalins and their antisense peptides were studied by electrospray ionization mass spectrometry. Mixtures of sense and antisense peptides gave both the corresponding homodimers and heterodimers. The relative abundance ratios of the heterodimer to that of the homodimer of the sense peptide and the relative stability constants of the heterodimers were compared with the corresponding values from mixtures of the sense peptides and a control peptide. The results show that there is a preferential interaction between the sense and antisense peptides compared with that between the sense and control peptides.

Antisense Elements (Genetics)↗