Novel anti-microbial peptidomimetic compounds and methods to calculate anti-microbial activity

Abstract

This invention encompasses synthetic antimicrobial peptide analogs having certain un-natural amino acids, including the un-natural amino acids hydrophobic tetrahydroisoquinolinecarboxylic acid (Tic) and octahydroindolecarboxylic acid (Oic), incorporated into the polypeptide backbone. These antimicrobial peptides (AMPs) are useful to treat infection in humans and other mammals of such bacteria as Gram positive bacteria, Gram negative bacteria and Mycobacterium . Many of the AMPs also exhibit the property of reduced hemolytic activity. The invention also entails 3D-QSAR models and mathematical equations that calculate the biological activity of any peptide sequence against Staphylococcus aureus or Mycobacterium ranae.

1 - 16 . (canceled) 
     
     
         17 . A synthetic peptide with bioactivity against  Staphylococcus aureus  (SA) satisfying at least four terms of the mathematical equation: SA predicted bioactivity=[(−1.4959דFcharge”)+(0.0098דdipole-mag”)+(0.0140דJurs-SASA”)+(0.0023דJurs-PPSA-1”)+(0.1876דJurs-PNSA-1”)+(0.0022דJurs-PNSA-2”)+(0.00037דJurs-DPSA-2”)+(0.0015דJurs-DPSA-3”)+(438.251דJurs-FPSA-1”)+(267.258דJurs-FPSA-3”)+(120.432דJurs-FNSA-3”)−(715.316דJurs-RPCG”)−(12.8649דJurs-RPCS”)−(0.0658דJurs-TASA”)−(125.513דJurs-RPSA”)+(125.513דJurs-RASA”)−(183.99דdensity”)+(1.0340דHbond acceptor”)+(0.0395דHbond donor”)−(0.3069דRotlbonds”)+(0.1148דA log P”)−(0.10004דRadOfGyration”)−225.589]. 
     
     
         18 . The synthetic peptide with bioactivity against  Staphylococcus aureus  (SA) according to  claim 17 , satisfying the mathematical equation: SA predicted bioactivity=[(−1.49592דFcharge”)+(0.0098147דdipole-mag”)+(0.013993דJurs-SASA”)+(0.00233דJurs-PPSA-1”)+(0.187647דJurs-PNSA-1”)+(0.0021686דJurs-PNSA-2”)+(0.00036919דJurs-DPSA-2”)+(0.0015025דJurs-DPSA-3”)+(438.251דJurs-FPSA-1”)+(267.258דJurs-FPSA-3”)+(120.432דJurs-FNSA-3”)−(715.316דJurs-RPCG”)−12.8649דJurs-RPCS”)−(0.065752דJurs-TASA”)−(125.513דJurs-RPSA”)+(125.513דJurs-RASA”)−(183.99דdensity”)+(1.03397דHbond acceptor”)+(0.039473דHbond donor”)−(0.306856דRotlbonds”)+(0.114808דA log P”)−(0.10004דRadOfGyration”)−225.589. 
     
     
         19 . The synthetic peptide with bioactivity against  Staphylococcus aureus  (SA) according to  claim 17 , having at least four of the following physicochemical properties, wherein the respective percentages of each property indicate the relative contribution toward the bioactivity: Jurs-FPSA-1—29.347%; density—16.010%; Jurs-TASA—14.762%; Jurs-PNSA-1—10.540%; Jurs-RASA—7.886%; Jurs-SASA—4.120%; Jurs-DPSA-2—3.093%; Jurs-PNSA-2—2.911%; Jurs-RPSA—2.492%; Rotlbonds—2.164%; Hbond acceptor—1.910%; Jurs-FPSA-3—1.709%; Fcharge—0.742%; Jurs-RPCG—0.726%; Jurs-PPSA-1—0.555%; Jurs-FNSA-3—0.426%; Dipole-mag—0.162%; RadOfGyration—0.127%; Jurs-RPCS−0.126%; Hbond donor—0.113%; Jurs-DPSA-3—0.053%; and A log P—0.026%. 
     
     
         20 . A synthetic peptide with bioactivity against  Mycobacterium  ranae (MR) satisfying at least four terms of the mathematical equation: MR predicted activity=[(−0.0084דconformer energy”)+(2.0576דFcharge”)+(0.00005דApol”)+(0.0061דdipole-mag”)−(0.0239דJurs-PPSA-1”)−(0.0083דJurs-PNSA-1”)+(0.00005דJurs-PPSA-2”)+(0.00019דJurs-PNSA-2”)−(18.282דJurs-FPSA-1”)+(13.321*“Jurs-FNSA-3”)−(8.4684דJurs-RPCG”)+(66.6262דJurs-RNCG”)+(0.0529דJurs-TPSA”)−(96.9761דJurs-RPSA”)+(96.9761דJurs-RASA”)−(127.577דdensity”)+(0.7687דHbond acceptor”)−(0.4983דHbond donor”)−(0.0608דRotlbonds”)−(0.0758דA log P”)+(0.3378דRadOfGyration”)+110.841]. 
     
     
         21 . A synthetic peptide with bioactivity against  Mycobacterium  ranae (MR) according to  claim 20 , satisfying the mathematical equation: MR predicted activity=[(−0.0083585דconformer energy”)+(2.05758דFcharge”)+(5.3259e-05דApol”)+(0.0061422דdipole-mag”)−(0.023941דJurs-PPSA-1”)−(0.008252דJurs-PNSA-1”)+(5.5381e-05דJurs-PPSA-2”)+(0.00018566דJurs-PNSA-2”)−(18.282דJurs-FPSA-1”)+(13.321*“Jurs-FNSA-3”)−(8.46841דJurs-RPCG”)+(66.6262דJurs-RNCG”)+(0.052889דJurs-TPSA”)−(96.9761דJurs-RPSA”)+(96.9761דJurs-RASA”)−(127.577דdensity”)+(0.768698דHbond acceptor”)−(0.498282דHbond donor”)−(0.060764דRotlbonds”)−(0.075759דA log P”)+(0.337835דRadOfGyration”)+110.841]. 
     
     
         22 . A synthetic peptide with bioactivity against  Mycobacterium  ranae (MR) according to  claim 20 , having at least four of the following physicochemical properties, wherein the respective percentages of each property indicate the relative contribution toward the bioactivity: Density—30.784%; Jurs-RASA—16.827%; Jurs-PPSA-1—15.494%; Jurs-TPSA—10.218%; Jurs-RPSA—5.444%; Hbond donor—3.905%; Hbond acceptor—3.729%; Jurs-FPSA-1—3.409%; Fcharge—2.892%: Jurs-PNSA-1—1.244%; RadOfGyration—1.164%; Rotlbonds—1.156%; Apol—1.148%; Jurs-PPSA-2—1.016%; Jurs-PNSA-2—0.632%; Jurs-RNCG—0.400%; Dipole-mag—0.298%; Jurs-FNSA-3—0.127%; A log P—0.051%; Conformer Energy—0.037%; Jurs-RPCG—0.024%; and Jurs-DPSA-2—0.00%. 
     
     
         23 . A method for determining whether a synthetic peptide is bioactive against  Staphylococcus aureus  (SA), comprising the steps of:
 i) determining the shape of a peptide that has minimum potential energy of the peptide;   ii) computing the conformational model for the peptide using standard Monte Carlo or molecular dynamics conformational search algorithms, so as to generate a pool of peptide conformations that are within 20 Kcals/mol energy range of the global minimum conformation;   iii) selecting from the peptide conformations of step ii) the conformation having the maximum measurement of its backbone when measured from head to tail, which conformation is within five Kcals/mole energy range of the global minimum conformer;   iv) aligning all conformations of step ii) with the selected conformation of step iii), wherein the selected comformation is used as a template structure;   v) determining the physicochemical properties for all the aligned conformations, wherein the physicochemical properties determined are conformer energy, Fcharge, dipole-mag, Jurs-SASA, Jurs-PPSA-1, Jurs-PNSA-1, Jurs-PNSA-2, Jurs-DPSA-2, Jurs-DPSA-3, Jurs-FPSA-1, Jurs-FPSA-3, Jurs-FNSA-3, Jurs-RPCG, Jurs-RPCS, Jurs-TASA, Jurs-RPSA, Jurs-RASA, density, Hbond acceptor, Hbond donor, Rotlbonds, A log P, and RadOfGyration; and   vi) applying a mathematical equation to each aligned conformation peptide, to  Staphylococcus aureus  (SA), which mathematical equation is: SA bioactivity equals satisfaction of at least four of the following terms: [(−1.49592דFcharge”)+(0.0098147דdipole-mag”)+(0.013993דJurs-SASA”)+(0.00233דJurs-PPSA-1”)+(0.187647דJurs-PNSA-1”)+(0.0021686דJurs-PNSA-2”)+(0.00036919דJurs-DPSA-2”)+(0.0015025דJurs-DPSA-3”)+(438.251דJurs-FPSA-1”)+(267.258דJurs-FPSA-3”)+(120.432דJurs-FNSA-3”)−(715.316דJurs-RPCG”)−12.8649דJurs-RPCS”)−(0.065752דJurs-TASA”)−(125.513דJurs-RPSA”)+(125.513דJurs-RASA”)−(183.99דdensity”)+(1.03397דHbond acceptor”)+(0.039473דHbond donor”)−(0.306856דRotlbonds”)+(0.114808דA log P”)−(0.10004דRadOfGyration”)−225.589.   
     
     
         24 . A method for determining whether a synthetic peptide is bioactive against  Mycobacterium ranae  (MR), comprising the steps of:
 i) determining the shape of a peptide that has minimum potential energy of the peptide;   ii) computing the conformational model for the peptide using standard Monte Carlo or molecular dynamics conformational search algorithms, so as to generate a pool of peptide conformations that are within 20 Kcals/mol energy range of the global minimum conformation;   iii) selecting from the peptide conformations of step ii) the conformation having the maximum measurement of its backbone when measured from head to tail, which conformation is within five Kcals/mole energy range of the global minimum conformer;   iv) aligning all conformations of step ii) with the selected conformation of step iii), wherein the selected comformation is used as a template structure;   v) determining the physicochemical properties for all the aligned conformations, wherein the physicochemical properties determined are conformer energy, Fcharge, Apol, dipole-mag, Jurs-PPSA-1, Jurs-PNSA-1, Jurs-PPSA-2, Jurs-PNSA-2, Jurs-FPSA-1, Jurs-FNSA-3, Jurs-RPCG, Jurs-RNCG, Jurs-TPSA, Jurs-RPSA, Jurs-RASA, density, Hbond acceptor, Hbond donor, Rotlbonds, A log P, and RadOfGyration; and   vi) applying a mathematical equation to each aligned conformation peptide, to determine whether the synthetic peptide is bioactive against  Mycobacterium ranae  (MR), which mathematical equation is: MR bioactivity equals satisfaction of at least four of the following terms: [(−0.0083585דconformer energy”)+(2.05758דFcharge”)+(5.3259e-05דApol”)+(0.0061422דdipole-mag”)−(0.023941דJurs-PPSA-1”)−(0.008252דJurs-PNSA-1”)+(5.5381e-05דJurs-PPSA-2”)+(0.00018566דJurs-PNSA-2”)−(18.282דJurs-FPSA-1”)+(13.321*“Jurs-FNSA-3”)−(8.46841דJurs-RPCG”)+(66.6262דJurs-RNCG”)+(0.052889דJurs-TPSA”)−(96.9761דJurs-RPSA”)+(96.9761דJurs-RASA”)−(127.577דdensity”)+(0.768698דHbond acceptor”)−(0.498282דHbond donor”)−(0.060764דRotlbonds”)−(0.075759דA log P”)+(0.337835דRadOfGyration”)+110.841].